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Entry
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- *161560 - INTERLEUKIN 12A; IL12A
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- OMIM
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<p>
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<span class="h4">*161560</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000168811;t=ENST00000699704" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=3592" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=161560" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000168811;t=ENST00000699704" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000882,NM_001354582,NM_001354583,NM_001397992" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001397992" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=161560" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01193&isoform_id=01193_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/IL12A" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/180624,189234,2944078,2944079,4323579,5923853,15128215,20141534,24430219,85397858,85397861,119599062,119599063,119599064,134273964,308381002,329602723,1231293770,1231293803,2160904175" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P29459" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=3592" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000168811;t=ENST00000699704" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL12A" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=IL12A" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+3592" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/IL12A" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:3592" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/3592" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000699704.1&hgg_start=159988835&hgg_end=159996019&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=161560[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=161560[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000168811" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=IL12A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=IL12A" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=IL12A&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA29784" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:5969" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:96539" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/IL12A#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:96539" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/3592/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3592" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060724-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:3592" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=IL12A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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161560
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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INTERLEUKIN 12A; IL12A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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IL12, p35 SUBUNIT<br />
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CYTOTOXIC LYMPHOCYTE MATURATION FACTOR; CLMF<br />
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NATURAL KILLER CELL STIMULATORY FACTOR, 35-KD SUBUNIT; NKSF1<br />
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IL35, p35 SUBUNIT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=IL12A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">IL12A</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/3/822?start=-3&limit=10&highlight=822">3q25.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:159988835-159996019&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:159,988,835-159,996,019</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>IL12A, or p35, is a subunit in 2 distinct heterodimeric cytokines: interleukin-12 (IL12) and IL35. IL12 is composed of 40-kD (p40, or IL12B; <a href="/entry/161561">161561</a>) and 35-kD (p35) subunits and functions to activate and link the innate and acquired immune responses (<a href="#21" class="mim-tip-reference" title="Wolf, S. F., Sieburth, D., Sypek, J. <strong>Interleukin 12: a key modulator of immune function.</strong> Stem Cells 12: 154-168, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7911046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7911046</a>] [<a href="https://doi.org/10.1002/stem.5530120203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7911046">Wolf et al., 1994</a>). IL35, an inhibitory cytokine involved in regulatory T-cell function, is composed of Epstein-Barr virus (EBV)-induced gene-3 (EBI3; <a href="/entry/605816">605816</a>) and the ubiquitously expressed p35 subunit of IL12 (<a href="#15" class="mim-tip-reference" title="Niedbala, W., Wei, X., Cai, B., Hueber, A. J., Leung, B. P., McInnes, I. B., Liew, F. Y. <strong>IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells.</strong> Europ. J. Immun. 37: 3021-3029, 2007. Note: Erratum: Europ. J. Immun. 37: 3293 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17874423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17874423</a>] [<a href="https://doi.org/10.1002/eji.200737810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17874423">Niedbala et al., 2007</a>; <a href="#2" class="mim-tip-reference" title="Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg, R. S., Vignali, D. A. A. <strong>The inhibitory cytokine IL-35 contributes to regulatory T-cell function.</strong> Nature 450: 566-569, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18033300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18033300</a>] [<a href="https://doi.org/10.1038/nature06306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18033300">Collison et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7911046+17874423+18033300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>IL12 (formerly NKSF, for natural killer cell stimulatory factor, or CLMF, for cytotoxic lymphocyte maturation factor) is a novel cytokine cloned from B-cell lines. It has a broad array of potent biologic activities, acting at picomolar and subpicomolar levels on both T and NK cells. IL12 is a disulfide-linked heterodimer composed of unrelated p40 and p35 subunits (<a href="#22" class="mim-tip-reference" title="Wolf, S. F., Temple, P. A., Kobayashi, M., Young, D., Dicig, M., Lowe, L., Dzialo, R., Fitz, L., Ferenz, C., Hewick, R. M., Kelleher, K., Herrmann, S. H., Clark, S. C., Azzoni, L., Chan, S. H., Trinchieri, G., Perussia, B. <strong>Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells.</strong> J. Immun. 146: 3074-3081, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673147</a>]" pmid="1673147">Wolf et al., 1991</a>). Sequence comparisons showed that p40 is a member of the cytokine receptor family most closely related to IL6R (<a href="/entry/147880">147880</a>) and forms a subgroup with IL6R and GCSFR (<a href="/entry/138971">138971</a>). On the other hand, p35 is related in sequence to ligands of the cytokine receptor family, most closely to IL6 (<a href="/entry/147620">147620</a>) and GCSF (<a href="/entry/138970">138970</a>). <a href="#10" class="mim-tip-reference" title="Gubler, U., Chua, A. O., Schoenhaut, D. S., Dwyer, C. M., McComas, W., Motyka, R., Nabavi, N., Wolitzky, A. G., Quinn, P. M., Familletti, P. C., Gately, M. K. <strong>Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor.</strong> Proc. Nat. Acad. Sci. 88: 4143-4147, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674604</a>] [<a href="https://doi.org/10.1073/pnas.88.10.4143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1674604">Gubler et al. (1991)</a> cloned and expressed cDNAs for both subunits of IL12 from a lymphoblastoid B-cell line. They showed that their mRNAs are coordinately induced upon activation of these cells and that coexpression of the 2-subunit cDNAs in COS cells is necessary for the secretion of biologically active CLMF. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1673147+1674604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By Southern blot and PCR analysis of DNA from rodent/human cell hybrids containing translocation chromosomes, <a href="#18" class="mim-tip-reference" title="Sieburth, D., Jabs, E. W., Warrington, J. A., Li, X., Lasota, J., LaForgia, S., Kelleher, K., Huebner, K., Wasmuth, J. J., Wolf, S. F. <strong>Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5.</strong> Genomics 14: 59-62, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1358798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1358798</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80283-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1358798">Sieburth et al. (1992)</a> localized IL12A, the gene encoding the p35 subunit, to 3p12-q13.2. The gene for the p40 subunit (IL12B) maps to 5q31-q33. <a href="#17" class="mim-tip-reference" title="Schweitzer, P. A., Noben-Trauth, N., Pelsue, S. C., Johnson, K. R., Wolf, S. F., Shultz, L. D. <strong>Genetic mapping of the IL-12 alpha chain gene (Il12a) on mouse chromosome 3.</strong> Mammalian Genome 7: 394-395, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661735</a>] [<a href="https://doi.org/10.1007/s003359900115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661735">Schweitzer et al. (1996)</a> found that the Il12a gene maps to mouse chromosome 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1358798+8661735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Interleukin-12</em></strong></p><p>
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In a review, <a href="#21" class="mim-tip-reference" title="Wolf, S. F., Sieburth, D., Sypek, J. <strong>Interleukin 12: a key modulator of immune function.</strong> Stem Cells 12: 154-168, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7911046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7911046</a>] [<a href="https://doi.org/10.1002/stem.5530120203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7911046">Wolf et al. (1994)</a> referred to interleukin-12 as a key modulator of immune function and discussed therapeutic potential in certain infections and cancers. Among the remaining questions was that of the function of the secreted p40. In a review of an NIH-sponsored meeting on IL12 as a potential therapeutic agent and vaccine adjuvant, <a href="#11" class="mim-tip-reference" title="Hall, S. S. <strong>IL-12 at the crossroads.</strong> Science 268: 1432-1434, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7770767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7770767</a>] [<a href="https://doi.org/10.1126/science.7770767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7770767">Hall (1995)</a> outlined the remarkably broad powers of this immune molecule against infections such as AIDS, malaria, and tuberculosis, but the fear was expressed that 'market forces may inhibit its development.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7911046+7770767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Schwarz, A., Stander, S., Berneburg, M., Bshm, M., Kulms, D., van Steeg, H., Grosse-Heitmeyer, K., Krutmann, J., Schwarz, T. <strong>Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair.</strong> Nature Cell Biol. 4: 26-31, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11780128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11780128</a>] [<a href="https://doi.org/10.1038/ncb717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11780128">Schwarz et al. (2002)</a> showed that preincubation of a variety of human cell lines with IL12 inhibited apoptosis induced by ultraviolet B (UVB) radiation, but not apoptosis induced by gamma irradiation. Immunohistochemistry revealed that intracutaneous injection of IL12 also reduced UVB-induced DNA damage and the number of sunburn cells in mouse skin. The number of apoptotic keratinocytes was higher in Il12a knockout mice than in controls. Because these protective effects of IL12 were not apparent immediately after UVB exposure, <a href="#16" class="mim-tip-reference" title="Schwarz, A., Stander, S., Berneburg, M., Bshm, M., Kulms, D., van Steeg, H., Grosse-Heitmeyer, K., Krutmann, J., Schwarz, T. <strong>Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair.</strong> Nature Cell Biol. 4: 26-31, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11780128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11780128</a>] [<a href="https://doi.org/10.1038/ncb717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11780128">Schwarz et al. (2002)</a> reasoned that IL12 might induce DNA repair. This conclusion was supported by comet assays, RNase protection analysis, and by the failure of Xpa (<a href="/entry/611153">611153</a>)-deficient mice, which are severely deficient in nucleotide excision repair capacity, to be protected by IL12 treatment. <a href="#16" class="mim-tip-reference" title="Schwarz, A., Stander, S., Berneburg, M., Bshm, M., Kulms, D., van Steeg, H., Grosse-Heitmeyer, K., Krutmann, J., Schwarz, T. <strong>Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair.</strong> Nature Cell Biol. 4: 26-31, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11780128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11780128</a>] [<a href="https://doi.org/10.1038/ncb717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11780128">Schwarz et al. (2002)</a> concluded that IL12 inhibits sunburn cell formation by reducing UVB-induced DNA damage and promoting DNA repair. They also proposed that overexpression of IL12 may be useful in preventing UV-induced skin cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11780128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Ferlazzo, G., Thomas, D., Lin, S. L., Goodman, K., Morandi, B., Muller, W. A., Moretta, A., Munz, C. <strong>The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.</strong> J. Immun. 172: 1455-1462, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14734722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14734722</a>] [<a href="https://doi.org/10.4049/jimmunol.172.3.1455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14734722">Ferlazzo et al. (2004)</a> observed that peripheral blood NK cells have a CD56 (NCAM1; <a href="/entry/116930">116930</a>)-dim/CD16 (FCGR3A; <a href="/entry/146740">146740</a>)-positive phenotype and express perforin (<a href="/entry/170280">170280</a>), the natural cytotoxicity receptors (NCRs) NKp30 (NCR3; <a href="/entry/611550">611550</a>) and NKp46 (NCR1; <a href="/entry/604530">604530</a>), and, in part, killer cell Ig-like receptors (KIRs, see <a href="/entry/604936">604936</a>). In contrast, lymph node NK cells have mainly a CD56-bright/CD16-negative phenotype and lack perforin, KIRs, and NCRs, except for low levels of NKp46. Tonsilar NK cells also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 (NCR2; <a href="/entry/604531">604531</a>) and NKp46. <a href="#8" class="mim-tip-reference" title="Ferlazzo, G., Thomas, D., Lin, S. L., Goodman, K., Morandi, B., Muller, W. A., Moretta, A., Munz, C. <strong>The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.</strong> J. Immun. 172: 1455-1462, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14734722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14734722</a>] [<a href="https://doi.org/10.4049/jimmunol.172.3.1455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14734722">Ferlazzo et al. (2004)</a> found that IL2 (<a href="/entry/147680">147680</a>) stimulation leads lymph node and tonsilar NK cells to upregulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL2 activation and therefore display a phenotype similar to peripheral blood NK cells. <a href="#8" class="mim-tip-reference" title="Ferlazzo, G., Thomas, D., Lin, S. L., Goodman, K., Morandi, B., Muller, W. A., Moretta, A., Munz, C. <strong>The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.</strong> J. Immun. 172: 1455-1462, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14734722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14734722</a>] [<a href="https://doi.org/10.4049/jimmunol.172.3.1455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14734722">Ferlazzo et al. (2004)</a> hypothesized that IL2 can mobilize NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. They also showed that NK cells isolated from lymphoid tissues produce IFNG after activation by IL2 and IL12. The results suggested that secondary lymphoid organs are possible sites of NK-cell differentiation and self-tolerance acquisition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14734722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunofluorescent microscopy, <a href="#7" class="mim-tip-reference" title="Ferlazzo, G., Pack, M., Thomas, D., Paludan, C., Schmid, D., Strowig, T., Bougras, G., Muller, W. A., Moretta, L., Munz, C. <strong>Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs.</strong> Proc. Nat. Acad. Sci. 101: 16606-16611, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15536127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15536127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15536127[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407522101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15536127">Ferlazzo et al. (2004)</a> demonstrated that NK cells and DEC205 (LY75; <a href="/entry/604524">604524</a>)-positive dendritic cells (DCs) are localized in T- rather than B-cell areas of normal human lymph nodes. They showed that DEC205-positive DCs induce IFNG expression by lymph node NK cells through IL12, whereas IL15 (<a href="/entry/600554">600554</a>) expressed at the DC surface mediates lymph node NK cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15536127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, <a href="#12" class="mim-tip-reference" title="Maier, B., Leader, A. M., Chen, S. T., Tung, N., Chang, C., LeBerichel, J., Chudnovskiy, A., Maskey, S., Walker, L., Finnigan, J. P., Kirkling, M. E., Reizis, B., and 11 others. <strong>A conserved dendritic-cell regulatory program limits antitumour immunity.</strong> Nature 580: 257-262, 2020. Note: Erratum: Nature 582: E17, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32269339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32269339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32269339[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2134-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32269339">Maier et al. (2020)</a> identified a cluster of dendritic DCs that they named 'mature dendritic cells enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes and maturation genes. <a href="#12" class="mim-tip-reference" title="Maier, B., Leader, A. M., Chen, S. T., Tung, N., Chang, C., LeBerichel, J., Chudnovskiy, A., Maskey, S., Walker, L., Finnigan, J. P., Kirkling, M. E., Reizis, B., and 11 others. <strong>A conserved dendritic-cell regulatory program limits antitumour immunity.</strong> Nature 580: 257-262, 2020. Note: Erratum: Nature 582: E17, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32269339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32269339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32269339[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2134-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32269339">Maier et al. (2020)</a> found that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumor antigens and further found that upregulation of PDL1 (<a href="/entry/605402">605402</a>), a key checkpoint molecule, in mregDCs is induced by the receptor tyrosine kinase AXL (<a href="/entry/109135">109135</a>), while upregulation of IL12 depends strictly on interferon-gamma (IFNG; <a href="/entry/147570">147570</a>) and is controlled negatively by IL4 (<a href="/entry/147780">147780</a>) signaling. Blocking IL4 enhances IL12 production by tumor antigen-bearing mregDC1s, expands the pool of tumor-infiltrating effector T cells, and reduces tumor burden. <a href="#12" class="mim-tip-reference" title="Maier, B., Leader, A. M., Chen, S. T., Tung, N., Chang, C., LeBerichel, J., Chudnovskiy, A., Maskey, S., Walker, L., Finnigan, J. P., Kirkling, M. E., Reizis, B., and 11 others. <strong>A conserved dendritic-cell regulatory program limits antitumour immunity.</strong> Nature 580: 257-262, 2020. Note: Erratum: Nature 582: E17, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32269339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32269339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32269339[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2134-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32269339">Maier et al. (2020)</a> concluded that they uncovered a regulatory module associated with tumor-antigen uptake that reduces DC1 functionality in human and mouse cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32269339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Interleukin-35</em></strong></p><p>
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By coimmunoprecipitation analysis, <a href="#5" class="mim-tip-reference" title="Devergne, O., Birkenbach, M., Kieff, E. <strong>Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin.</strong> Proc. Nat. Acad. Sci. 94: 12041-12046, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.22.12041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9342359">Devergne et al. (1997)</a> found that EBI3 specifically associated with the p35 subunit of IL12 in lysates and culture media of transfected EBV-negative Burkitt lymphoma cells and COS-7 cells. Coexpression of EBI3 and p35 mutually facilitated their secretion. A large fraction of p35 in human placental trophoblasts specifically coimmunoprecipitated with EBI3, indicating that EBI3 and p35 form a heterodimer in vivo. Because EBI3 is expressed in EBV-transformed B lymphocytes, spleen, tonsil, and placental trophoblasts, <a href="#5" class="mim-tip-reference" title="Devergne, O., Birkenbach, M., Kieff, E. <strong>Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin.</strong> Proc. Nat. Acad. Sci. 94: 12041-12046, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.22.12041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9342359">Devergne et al. (1997)</a> suggested that the EBI3/p35 heterodimer is likely to be an important immunomodulator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Niedbala, W., Wei, X., Cai, B., Hueber, A. J., Leung, B. P., McInnes, I. B., Liew, F. Y. <strong>IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells.</strong> Europ. J. Immun. 37: 3021-3029, 2007. Note: Erratum: Europ. J. Immun. 37: 3293 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17874423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17874423</a>] [<a href="https://doi.org/10.1002/eji.200737810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17874423">Niedbala et al. (2007)</a> covalently linked EBI3 with the p35-Fc fusion protein in human and mouse to form the heterodimeric protein IL35. Western blot analysis detected human IL35 at 78 kD. Stimulation of mouse Cd4 (<a href="/entry/186940">186940</a>)-positive/Cd25 (IL2RA; <a href="/entry/147730">147730</a>)-negative effector T cells with IL35 plus anti-Cd3 (see <a href="/entry/186740">186740</a>) and anti-Cd28 (<a href="/entry/186760">186760</a>) antibodies induced proliferation, Ifng production, and Tbet (TBX21; <a href="/entry/604895">604895</a>) expression. In contrast, IL35 stimulation of mouse Cd4-positive/Cd25-negative regulatory T (Treg) cells induced proliferation and Il10 (<a href="/entry/124092">124092</a>) production without inducing additional Foxp3 (<a href="/entry/300292">300292</a>) expression. IL35-expanded Cd4-positive/Cd25-positive T cells suppressed Cd4-positive/Cd25-negative T-cell proliferation. IL35, but not EBI3 alone, inhibited differentiation of mouse Cd4-positive T cells into Il17 (<a href="/entry/603149">603149</a>)-producing Th17 cells. Treatment of mice with collagen-induced arthritis with IL35 resulted in lower disease incidence, fewer arthritic paws, reduced pathology, increased serum Il10 and Ifng, and less inducible Il17. The effect of IL35 on arthritis was comparable to that mediated by soluble TNFR (<a href="/entry/191190">191190</a>), the standard treatment for clinical rheumatoid arthritis. <a href="#15" class="mim-tip-reference" title="Niedbala, W., Wei, X., Cai, B., Hueber, A. J., Leung, B. P., McInnes, I. B., Liew, F. Y. <strong>IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells.</strong> Europ. J. Immun. 37: 3021-3029, 2007. Note: Erratum: Europ. J. Immun. 37: 3293 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17874423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17874423</a>] [<a href="https://doi.org/10.1002/eji.200737810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17874423">Niedbala et al. (2007)</a> concluded that IL35 is an antiinflammatory cytokine that induces both Treg cells and Th1 cells, but suppresses Th17 cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17874423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By functional genomic screening, RT-PCR, and FACS analysis, <a href="#2" class="mim-tip-reference" title="Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg, R. S., Vignali, D. A. A. <strong>The inhibitory cytokine IL-35 contributes to regulatory T-cell function.</strong> Nature 450: 566-569, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18033300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18033300</a>] [<a href="https://doi.org/10.1038/nature06306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18033300">Collison et al. (2007)</a> found increased expression of Ebi3 and Il12a in Foxp3-positive mouse Treg cells compared with effector T cells. Immunoblot analysis showed coimmunoprecipitation of Ebi3 and Il12a in Treg cells, but not in effector T cells. Transcription analysis identified Ebi3 as a downstream target of Foxp3. Transfer of wildtype Treg cells, but not Ebi3 -/- or Il12a -/- Treg cells, to T cell-reconstituted Rag1 (<a href="/entry/179615">179615</a>) -/- mice with colitis (see <a href="/entry/266600">266600</a>) restored appetite and weight gain and reduced inflammatory pathology. <a href="#2" class="mim-tip-reference" title="Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg, R. S., Vignali, D. A. A. <strong>The inhibitory cytokine IL-35 contributes to regulatory T-cell function.</strong> Nature 450: 566-569, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18033300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18033300</a>] [<a href="https://doi.org/10.1038/nature06306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18033300">Collison et al. (2007)</a> concluded that IL35 is an inhibitory cytokine produced by Treg cells that contributes to their suppressive activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18033300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>IL12 favors T helper-1 (Th1) differentiation. Th1 lymphocytes prevail over Th2 in the chronic gastritis associated with H. pylori infection, the first step in H. pylori-associated gastric carcinogenesis. <a href="#14" class="mim-tip-reference" title="Navaglia, F., Basso, D., Zambon, C.-F., Ponzano, E., Caenazzo, L., Gallo, N., Falda, A., Belluco, C., Fogar, P., Greco, E., Di Mario, F., Rugge, M., Plebani, M. <strong>Interleukin 12 gene polymorphisms enhance gastric cancer risk in H pylori infected individuals. (Letter)</strong> J. Med. Genet. 42: 503-510, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937086</a>] [<a href="https://doi.org/10.1136/jmg.2004.022723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937086">Navaglia et al. (2005)</a> compared 110 patients with noncardia gastric cancer with 251 patients with benign gastroduodenal diseases to see whether there was any correlation between IL12 gene polymorphisms and H. pylori-associated gastric adenocarcinoma. They found that the frequency of noncardia gastric cancer was higher in patients with -504T/T homozygosity of IL12A (OR = 2.38) or with a particular VNTR of IL12B (OR = 1.36). No IL12 gene polymorphisms correlated with intestinal metaplasia. <a href="#14" class="mim-tip-reference" title="Navaglia, F., Basso, D., Zambon, C.-F., Ponzano, E., Caenazzo, L., Gallo, N., Falda, A., Belluco, C., Fogar, P., Greco, E., Di Mario, F., Rugge, M., Plebani, M. <strong>Interleukin 12 gene polymorphisms enhance gastric cancer risk in H pylori infected individuals. (Letter)</strong> J. Med. Genet. 42: 503-510, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937086</a>] [<a href="https://doi.org/10.1136/jmg.2004.022723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937086">Navaglia et al. (2005)</a> suggested that IL12A and IL12B gene polymorphisms may affect the final steps in gastric carcinogenesis in patients with H. pylori infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For discussion of a possible association between variation in the IL12A gene and primary biliary cirrhosis, see PBC1 (<a href="/entry/109720">109720</a>).</p>
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<p><a href="#6" class="mim-tip-reference" title="Diefenbach, A., Schindler, H., Rollinghoff, M., Yokoyama, W. M., Bogdan, C. <strong>Requirement for type 2 NO synthase for IL-12 signaling in innate immunity.</strong> Science 284: 951-955, 1999. Note: Erratum: Science 284: 1776 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10320373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10320373</a>] [<a href="https://doi.org/10.1126/science.284.5416.951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10320373">Diefenbach et al. (1999)</a> studied the relationship of IL12 and nitric oxide synthase-2 (NOS2; <a href="/entry/163730">163730</a>) to innate immunity to the parasite Leishmania in mice. In the absence of NOS2 activity, IL12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer cells for cytotoxicity or interferon-gamma (IFNG; <a href="/entry/147570">147570</a>) release, and failed to activate TYK2 (<a href="/entry/176941">176941</a>) and to tyrosine-phosphorylate STAT4 (<a href="/entry/600558">600558</a>), the central signal transducer of IL12, in NK cells. Activation of TYK2 in NK cells by IFN-alpha/beta (type I interferon; see <a href="/entry/107470">107470</a>) also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10320373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using female mice lacking either the Il12a or Il12b gene, <a href="#3" class="mim-tip-reference" title="Cooper, A. M., Kipnis, A., Turner, J., Magram, J., Ferrante, J., Orme, I. M. <strong>Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.</strong> J. Immun. 168: 1322-1327, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11801672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11801672</a>] [<a href="https://doi.org/10.4049/jimmunol.168.3.1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11801672">Cooper et al. (2002)</a> determined that both types of mice were more susceptible than wildtype mice to aerosol infection with virulent M. tuberculosis, but mice lacking Il12b were most susceptible and had increased mortality. This greater susceptibility for Il12b-deficient mice correlated with a reduced capacity to mount a delayed-type hypersensitivity response and a reduced ability to produce Ifng and to recruit activated lymphocytes (i.e., highly CD44 (<a href="/entry/107269">107269</a>)-positive) and Ifng-producing cells to the site of infection. RT-PCR analysis showed that the lungs of infected mice expressed increased levels of p19 (IL23A; <a href="/entry/605580">605580</a>), a protein complexed with IL12B to form IL23. Expression of p19 was maintained longer in both types of knockout mice than in controls. <a href="#3" class="mim-tip-reference" title="Cooper, A. M., Kipnis, A., Turner, J., Magram, J., Ferrante, J., Orme, I. M. <strong>Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.</strong> J. Immun. 168: 1322-1327, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11801672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11801672</a>] [<a href="https://doi.org/10.4049/jimmunol.168.3.1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11801672">Cooper et al. (2002)</a> proposed that p19 may be produced by dendritic cells after ligation of TLR2 (<a href="/entry/603028">603028</a>) with a 19-kd lipoprotein of M. tuberculosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11801672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Becher, B., Durell, B. G., Noelle, R. J. <strong>Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12.</strong> J. Clin. Invest. 110: 493-497, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12189243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189243">Becher et al. (2002)</a> found that p40 (IL12B) -/- mice showed no clinical evidence of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, after immunization with myelin oligodendrocyte glycoprotein 35-55 (MOG). In contrast, p35 (IL12A) -/- mice were highly susceptible to EAE, with manifestations more severe than in wildtype mice, including severe central nervous system (CNS) inflammation. RT-PCR analysis of CNS-infiltrating cells showed reduced Tnf (<a href="/entry/191160">191160</a>) and markedly increased Il4 (<a href="/entry/147780">147780</a>) and Il10 expression in p35 -/- mice compared with wildtype mice. <a href="#1" class="mim-tip-reference" title="Becher, B., Durell, B. G., Noelle, R. J. <strong>Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12.</strong> J. Clin. Invest. 110: 493-497, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12189243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189243">Becher et al. (2002)</a> concluded that p40 is critical for the development of EAE, but the IL12 p70 heterodimer is completely dispensable. They suggested that another molecule using p40, such as IL23, is likely to be involved in EAE pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>IL12 is composed of p35 (IL12A) and p40 (IL12B) subunits, while IL23 is composed of a p19 (IL23A) subunit and the IL12 p40 subunit. <a href="#4" class="mim-tip-reference" title="Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., Sedgwick, J. D. <strong>Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.</strong> Nature 421: 744-748, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12610626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12610626</a>] [<a href="https://doi.org/10.1038/nature01355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12610626">Cua et al. (2003)</a> generated mice lacking only IL23 (p19 -/-), only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them with MOG in an EAE model of multiple sclerosis. The p19 -/- mice were generated by completely removing the p19 locus. Mice lacking p19 or p40 were resistant to development of EAE, whereas mice lacking only p35 were at least as susceptible as wildtype mice. Exogenous IL23 delivered into the CNS, but not intravenously, 2 days before expected onset of disease reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in the latter was delayed and disease was less severe. Administration of recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8, also induced intense EAE, suggesting that IL12 promotes the development of Th1 cells, while IL23 is required for subsequent inflammatory events. MOG immunization induced Th1 cells and proinflammatory cytokines in p19 -/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was observed. Flow cytometric and real-time PCR analyses demonstrated the entry of Th1 cells into the CNS in the absence of IL23, without the recruitment of additional T cells or macrophages or the activation of resident microglia. During EAE, IL23R (<a href="/entry/607562">607562</a>) and IL12RB1 (<a href="/entry/601604">601604</a>) were coexpressed by inflammatory macrophages, whereas resident microglia expressed only IL12RB1. Although resident microglia and inflammatory macrophages produced IL23, only inflammatory macrophages responded to IL23. In contrast, IL12 was produced primarily by inflammatory macrophages, and both macrophages and microglia had the potential to respond to IL12. <a href="#4" class="mim-tip-reference" title="Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., Sedgwick, J. D. <strong>Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.</strong> Nature 421: 744-748, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12610626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12610626</a>] [<a href="https://doi.org/10.1038/nature01355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12610626">Cua et al. (2003)</a> concluded that IL12 promotes the development of naive T cells, while IL23 mediates late-stage inflammation and seems to be necessary for chronic inflammation. In a commentary, <a href="#20" class="mim-tip-reference" title="Watford, W. T., O'Shea, J. J. <strong>A case of mistaken identity.</strong> Nature 421: 706-707, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12610607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12610607</a>] [<a href="https://doi.org/10.1038/421706a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12610607">Watford and O'Shea (2003)</a> noted that IL12 now has an 'alibi' in the development of autoimmune disease and that previous studies attributing these deleterious effects to IL12 may need reevaluation, including precise determination of the role of each subunit in this family of dimeric cytokines. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12610607+12610626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Grabie, N., Delfs, M. W., Westrich, J. R., Love, V. A., Stavrakis, G., Ahmad, F., Seidman, C. E., Seidman, J. G., Lichtman, A. H. <strong>IL-12 is required for differentiation of pathogenic CD8-positive T cell effectors that cause myocarditis.</strong> J. Clin. Invest. 111: 671-680, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12618521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12618521</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12618521[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12618521">Grabie et al. (2003)</a> studied transgenic mice expressing cardiac myocyte-restricted membrane-bound ovalbumin (OVA), which are tolerant to OVA. They found that adoptively transferred OVA peptide-specific CD8 (see <a href="/entry/186910">186910</a>)-positive T cells could infiltrate the hearts of transgenic mice and induce lethal myocarditis only in the presence of vesicular stomatitis virus infection or when the T cells were first stimulated with OVA peptide in vitro in the presence of recombinant IL12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12618521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. <strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong> J. Exp. Med. 210: 2803-2811, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20130678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24277150">Vom Berg et al. (2013)</a> used a syngeneic mouse model for glioblastoma (GB; see <a href="/entry/137800">137800</a>) and administered cytokines in the tumor area to overcome the immunosuppressive GB microenvironment. The authors found that Il12, but not Il23, reversed GB-induced immunosuppression and led to tumor clearance in a T cell-dependent manner. To better replicate the human clinical situation, <a href="#19" class="mim-tip-reference" title="vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. <strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong> J. Exp. Med. 210: 2803-2811, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20130678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24277150">vom Berg et al. (2013)</a> delayed therapy until after GB progression. They found that intratumoral application of Il12 combined with systemic anti-Ctla4 (<a href="/entry/123890">123890</a>), but not monotherapy with either Il12 or anti-Ctla4, led to tumor eradication even at advanced disease stages. The Il12 and anti-Ctla4 combination treatment acted predominantly on Cd4-positive T cells, causing a drastic reduction in Foxp3-positive Tregs and an increase in effector T cells. <a href="#19" class="mim-tip-reference" title="vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. <strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong> J. Exp. Med. 210: 2803-2811, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20130678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24277150">Vom Berg et al. (2013)</a> proposed that the combination of intratumoral IL12 and anti-CTLA4 should be tested in clinical trials for treatment of GB and, possibly, other solid tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24277150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Merberg1992" class="mim-tip-reference" title="Merberg, D. M., Wolf, S. F., Clark, S. C. <strong>Sequence similarity between NKSF and the IL6/GCSF family. (Letter)</strong> Immun. Today 13: 77-78, 1992.">Merberg et al. (1992)</a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18033300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18033300</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18033300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature06306" target="_blank">Full Text</a>]
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Cooper, A. M., Kipnis, A., Turner, J., Magram, J., Ferrante, J., Orme, I. M.
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<strong>Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.</strong>
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J. Immun. 168: 1322-1327, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11801672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11801672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11801672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.168.3.1322" target="_blank">Full Text</a>]
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Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., Sedgwick, J. D.
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Nature 421: 744-748, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12610626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12610626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12610626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature01355" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9342359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10320373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10320373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10320373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.284.5416.951" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15536127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15536127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15536127[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15536127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0407522101" target="_blank">Full Text</a>]
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Ferlazzo, G., Thomas, D., Lin, S. L., Goodman, K., Morandi, B., Muller, W. A., Moretta, A., Munz, C.
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<strong>The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14734722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14734722</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14734722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.172.3.1455" target="_blank">Full Text</a>]
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Grabie, N., Delfs, M. W., Westrich, J. R., Love, V. A., Stavrakis, G., Ahmad, F., Seidman, C. E., Seidman, J. G., Lichtman, A. H.
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<strong>IL-12 is required for differentiation of pathogenic CD8-positive T cell effectors that cause myocarditis.</strong>
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J. Clin. Invest. 111: 671-680, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12618521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12618521</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12618521[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12618521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI16867" target="_blank">Full Text</a>]
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Gubler, U., Chua, A. O., Schoenhaut, D. S., Dwyer, C. M., McComas, W., Motyka, R., Nabavi, N., Wolitzky, A. G., Quinn, P. M., Familletti, P. C., Gately, M. K.
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[<a href="https://doi.org/10.1073/pnas.88.10.4143" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.7770767" target="_blank">Full Text</a>]
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<div class="">
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[<a href="https://doi.org/10.1038/s41586-020-2134-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0167-5699(92)90140-3" target="_blank">Full Text</a>]
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<div class="">
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Navaglia, F., Basso, D., Zambon, C.-F., Ponzano, E., Caenazzo, L., Gallo, N., Falda, A., Belluco, C., Fogar, P., Greco, E., Di Mario, F., Rugge, M., Plebani, M.
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[<a href="https://doi.org/10.1136/jmg.2004.022723" target="_blank">Full Text</a>]
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<a id="Niedbala2007" class="mim-anchor"></a>
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<div class="">
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Niedbala, W., Wei, X., Cai, B., Hueber, A. J., Leung, B. P., McInnes, I. B., Liew, F. Y.
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<strong>IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells.</strong>
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[<a href="https://doi.org/10.1002/eji.200737810" target="_blank">Full Text</a>]
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<a id="Schwarz2002" class="mim-anchor"></a>
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<strong>Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11780128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11780128</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11780128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncb717" target="_blank">Full Text</a>]
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<strong>Genetic mapping of the IL-12 alpha chain gene (Il12a) on mouse chromosome 3.</strong>
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[<a href="https://doi.org/10.1007/s003359900115" target="_blank">Full Text</a>]
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<a id="Sieburth1992" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/s0888-7543(05)80283-6" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24277150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1084/jem.20130678" target="_blank">Full Text</a>]
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<a id="Watford2003" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/421706a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/stem.5530120203" target="_blank">Full Text</a>]
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Wolf, S. F., Temple, P. A., Kobayashi, M., Young, D., Dicig, M., Lowe, L., Dzialo, R., Fitz, L., Ferenz, C., Hewick, R. M., Kelleher, K., Herrmann, S. H., Clark, S. C., Azzoni, L., Chan, S. H., Trinchieri, G., Perussia, B.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1673147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/10/2020
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<span class="mim-text-font">
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Paul J. Converse - updated : 10/21/2014<br>Marla J. F. O'Neill - updated : 7/10/2009<br>Paul J. Converse - updated : 12/11/2007<br>Matthew B. Gross - updated : 12/11/2007<br>Paul J. Converse - updated : 1/12/2006<br>Victor A. McKusick - updated : 7/6/2005<br>Paul J. Converse - updated : 2/25/2005<br>Paul J. Converse - updated : 2/22/2005<br>Paul J. Converse - updated : 2/12/2003<br>Paul J. Converse - updated : 4/18/2002<br>Paul J. Converse - updated : 2/19/2002<br>Ada Hamosh - updated : 11/28/2001<br>Ada Hamosh - updated : 5/5/1999
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Victor A. McKusick : 7/21/1992
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carol : 03/09/2022<br>carol : 03/08/2022<br>alopez : 08/10/2020<br>alopez : 08/10/2020<br>mgross : 10/21/2014<br>carol : 9/14/2012<br>terry : 6/6/2012<br>carol : 9/10/2009<br>terry : 7/10/2009<br>mgross : 12/11/2007<br>mgross : 12/11/2007<br>mgross : 10/24/2007<br>carol : 7/12/2007<br>mgross : 1/12/2006<br>wwang : 7/13/2005<br>wwang : 7/6/2005<br>mgross : 2/25/2005<br>mgross : 2/22/2005<br>mgross : 2/12/2003<br>mgross : 2/12/2003<br>mgross : 4/18/2002<br>terry : 3/6/2002<br>mgross : 2/19/2002<br>mgross : 2/19/2002<br>alopez : 1/7/2002<br>carol : 11/28/2001<br>terry : 11/28/2001<br>kayiaros : 7/13/1999<br>alopez : 5/7/1999<br>terry : 5/5/1999<br>dkim : 7/2/1998<br>mark : 3/11/1997<br>terry : 11/20/1996<br>mark : 10/25/1996<br>terry : 6/13/1996<br>terry : 6/11/1996<br>mark : 7/11/1995<br>jason : 7/1/1994<br>carol : 5/16/1994<br>carol : 10/26/1993<br>carol : 11/13/1992<br>carol : 10/19/1992
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<span class="mim-font">
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<strong>*</strong> 161560
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<h3>
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INTERLEUKIN 12A; IL12A
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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IL12, p35 SUBUNIT<br />
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CYTOTOXIC LYMPHOCYTE MATURATION FACTOR; CLMF<br />
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NATURAL KILLER CELL STIMULATORY FACTOR, 35-KD SUBUNIT; NKSF1<br />
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IL35, p35 SUBUNIT
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: IL12A</em></strong>
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<strong>
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<em>
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Cytogenetic location: 3q25.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:159,988,835-159,996,019 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>IL12A, or p35, is a subunit in 2 distinct heterodimeric cytokines: interleukin-12 (IL12) and IL35. IL12 is composed of 40-kD (p40, or IL12B; 161561) and 35-kD (p35) subunits and functions to activate and link the innate and acquired immune responses (Wolf et al., 1994). IL35, an inhibitory cytokine involved in regulatory T-cell function, is composed of Epstein-Barr virus (EBV)-induced gene-3 (EBI3; 605816) and the ubiquitously expressed p35 subunit of IL12 (Niedbala et al., 2007; Collison et al., 2007). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>IL12 (formerly NKSF, for natural killer cell stimulatory factor, or CLMF, for cytotoxic lymphocyte maturation factor) is a novel cytokine cloned from B-cell lines. It has a broad array of potent biologic activities, acting at picomolar and subpicomolar levels on both T and NK cells. IL12 is a disulfide-linked heterodimer composed of unrelated p40 and p35 subunits (Wolf et al., 1991). Sequence comparisons showed that p40 is a member of the cytokine receptor family most closely related to IL6R (147880) and forms a subgroup with IL6R and GCSFR (138971). On the other hand, p35 is related in sequence to ligands of the cytokine receptor family, most closely to IL6 (147620) and GCSF (138970). Gubler et al. (1991) cloned and expressed cDNAs for both subunits of IL12 from a lymphoblastoid B-cell line. They showed that their mRNAs are coordinately induced upon activation of these cells and that coexpression of the 2-subunit cDNAs in COS cells is necessary for the secretion of biologically active CLMF. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By Southern blot and PCR analysis of DNA from rodent/human cell hybrids containing translocation chromosomes, Sieburth et al. (1992) localized IL12A, the gene encoding the p35 subunit, to 3p12-q13.2. The gene for the p40 subunit (IL12B) maps to 5q31-q33. Schweitzer et al. (1996) found that the Il12a gene maps to mouse chromosome 3. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p><strong><em>Interleukin-12</em></strong></p><p>
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In a review, Wolf et al. (1994) referred to interleukin-12 as a key modulator of immune function and discussed therapeutic potential in certain infections and cancers. Among the remaining questions was that of the function of the secreted p40. In a review of an NIH-sponsored meeting on IL12 as a potential therapeutic agent and vaccine adjuvant, Hall (1995) outlined the remarkably broad powers of this immune molecule against infections such as AIDS, malaria, and tuberculosis, but the fear was expressed that 'market forces may inhibit its development.' </p><p>Schwarz et al. (2002) showed that preincubation of a variety of human cell lines with IL12 inhibited apoptosis induced by ultraviolet B (UVB) radiation, but not apoptosis induced by gamma irradiation. Immunohistochemistry revealed that intracutaneous injection of IL12 also reduced UVB-induced DNA damage and the number of sunburn cells in mouse skin. The number of apoptotic keratinocytes was higher in Il12a knockout mice than in controls. Because these protective effects of IL12 were not apparent immediately after UVB exposure, Schwarz et al. (2002) reasoned that IL12 might induce DNA repair. This conclusion was supported by comet assays, RNase protection analysis, and by the failure of Xpa (611153)-deficient mice, which are severely deficient in nucleotide excision repair capacity, to be protected by IL12 treatment. Schwarz et al. (2002) concluded that IL12 inhibits sunburn cell formation by reducing UVB-induced DNA damage and promoting DNA repair. They also proposed that overexpression of IL12 may be useful in preventing UV-induced skin cancer. </p><p>Ferlazzo et al. (2004) observed that peripheral blood NK cells have a CD56 (NCAM1; 116930)-dim/CD16 (FCGR3A; 146740)-positive phenotype and express perforin (170280), the natural cytotoxicity receptors (NCRs) NKp30 (NCR3; 611550) and NKp46 (NCR1; 604530), and, in part, killer cell Ig-like receptors (KIRs, see 604936). In contrast, lymph node NK cells have mainly a CD56-bright/CD16-negative phenotype and lack perforin, KIRs, and NCRs, except for low levels of NKp46. Tonsilar NK cells also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 (NCR2; 604531) and NKp46. Ferlazzo et al. (2004) found that IL2 (147680) stimulation leads lymph node and tonsilar NK cells to upregulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL2 activation and therefore display a phenotype similar to peripheral blood NK cells. Ferlazzo et al. (2004) hypothesized that IL2 can mobilize NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. They also showed that NK cells isolated from lymphoid tissues produce IFNG after activation by IL2 and IL12. The results suggested that secondary lymphoid organs are possible sites of NK-cell differentiation and self-tolerance acquisition. </p><p>Using immunofluorescent microscopy, Ferlazzo et al. (2004) demonstrated that NK cells and DEC205 (LY75; 604524)-positive dendritic cells (DCs) are localized in T- rather than B-cell areas of normal human lymph nodes. They showed that DEC205-positive DCs induce IFNG expression by lymph node NK cells through IL12, whereas IL15 (600554) expressed at the DC surface mediates lymph node NK cell proliferation. </p><p>Using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, Maier et al. (2020) identified a cluster of dendritic DCs that they named 'mature dendritic cells enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes and maturation genes. Maier et al. (2020) found that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumor antigens and further found that upregulation of PDL1 (605402), a key checkpoint molecule, in mregDCs is induced by the receptor tyrosine kinase AXL (109135), while upregulation of IL12 depends strictly on interferon-gamma (IFNG; 147570) and is controlled negatively by IL4 (147780) signaling. Blocking IL4 enhances IL12 production by tumor antigen-bearing mregDC1s, expands the pool of tumor-infiltrating effector T cells, and reduces tumor burden. Maier et al. (2020) concluded that they uncovered a regulatory module associated with tumor-antigen uptake that reduces DC1 functionality in human and mouse cancers. </p><p><strong><em>Interleukin-35</em></strong></p><p>
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By coimmunoprecipitation analysis, Devergne et al. (1997) found that EBI3 specifically associated with the p35 subunit of IL12 in lysates and culture media of transfected EBV-negative Burkitt lymphoma cells and COS-7 cells. Coexpression of EBI3 and p35 mutually facilitated their secretion. A large fraction of p35 in human placental trophoblasts specifically coimmunoprecipitated with EBI3, indicating that EBI3 and p35 form a heterodimer in vivo. Because EBI3 is expressed in EBV-transformed B lymphocytes, spleen, tonsil, and placental trophoblasts, Devergne et al. (1997) suggested that the EBI3/p35 heterodimer is likely to be an important immunomodulator. </p><p>Niedbala et al. (2007) covalently linked EBI3 with the p35-Fc fusion protein in human and mouse to form the heterodimeric protein IL35. Western blot analysis detected human IL35 at 78 kD. Stimulation of mouse Cd4 (186940)-positive/Cd25 (IL2RA; 147730)-negative effector T cells with IL35 plus anti-Cd3 (see 186740) and anti-Cd28 (186760) antibodies induced proliferation, Ifng production, and Tbet (TBX21; 604895) expression. In contrast, IL35 stimulation of mouse Cd4-positive/Cd25-negative regulatory T (Treg) cells induced proliferation and Il10 (124092) production without inducing additional Foxp3 (300292) expression. IL35-expanded Cd4-positive/Cd25-positive T cells suppressed Cd4-positive/Cd25-negative T-cell proliferation. IL35, but not EBI3 alone, inhibited differentiation of mouse Cd4-positive T cells into Il17 (603149)-producing Th17 cells. Treatment of mice with collagen-induced arthritis with IL35 resulted in lower disease incidence, fewer arthritic paws, reduced pathology, increased serum Il10 and Ifng, and less inducible Il17. The effect of IL35 on arthritis was comparable to that mediated by soluble TNFR (191190), the standard treatment for clinical rheumatoid arthritis. Niedbala et al. (2007) concluded that IL35 is an antiinflammatory cytokine that induces both Treg cells and Th1 cells, but suppresses Th17 cell differentiation. </p><p>By functional genomic screening, RT-PCR, and FACS analysis, Collison et al. (2007) found increased expression of Ebi3 and Il12a in Foxp3-positive mouse Treg cells compared with effector T cells. Immunoblot analysis showed coimmunoprecipitation of Ebi3 and Il12a in Treg cells, but not in effector T cells. Transcription analysis identified Ebi3 as a downstream target of Foxp3. Transfer of wildtype Treg cells, but not Ebi3 -/- or Il12a -/- Treg cells, to T cell-reconstituted Rag1 (179615) -/- mice with colitis (see 266600) restored appetite and weight gain and reduced inflammatory pathology. Collison et al. (2007) concluded that IL35 is an inhibitory cytokine produced by Treg cells that contributes to their suppressive activities. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>IL12 favors T helper-1 (Th1) differentiation. Th1 lymphocytes prevail over Th2 in the chronic gastritis associated with H. pylori infection, the first step in H. pylori-associated gastric carcinogenesis. Navaglia et al. (2005) compared 110 patients with noncardia gastric cancer with 251 patients with benign gastroduodenal diseases to see whether there was any correlation between IL12 gene polymorphisms and H. pylori-associated gastric adenocarcinoma. They found that the frequency of noncardia gastric cancer was higher in patients with -504T/T homozygosity of IL12A (OR = 2.38) or with a particular VNTR of IL12B (OR = 1.36). No IL12 gene polymorphisms correlated with intestinal metaplasia. Navaglia et al. (2005) suggested that IL12A and IL12B gene polymorphisms may affect the final steps in gastric carcinogenesis in patients with H. pylori infection. </p><p>For discussion of a possible association between variation in the IL12A gene and primary biliary cirrhosis, see PBC1 (109720).</p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Diefenbach et al. (1999) studied the relationship of IL12 and nitric oxide synthase-2 (NOS2; 163730) to innate immunity to the parasite Leishmania in mice. In the absence of NOS2 activity, IL12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer cells for cytotoxicity or interferon-gamma (IFNG; 147570) release, and failed to activate TYK2 (176941) and to tyrosine-phosphorylate STAT4 (600558), the central signal transducer of IL12, in NK cells. Activation of TYK2 in NK cells by IFN-alpha/beta (type I interferon; see 107470) also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity. </p><p>Using female mice lacking either the Il12a or Il12b gene, Cooper et al. (2002) determined that both types of mice were more susceptible than wildtype mice to aerosol infection with virulent M. tuberculosis, but mice lacking Il12b were most susceptible and had increased mortality. This greater susceptibility for Il12b-deficient mice correlated with a reduced capacity to mount a delayed-type hypersensitivity response and a reduced ability to produce Ifng and to recruit activated lymphocytes (i.e., highly CD44 (107269)-positive) and Ifng-producing cells to the site of infection. RT-PCR analysis showed that the lungs of infected mice expressed increased levels of p19 (IL23A; 605580), a protein complexed with IL12B to form IL23. Expression of p19 was maintained longer in both types of knockout mice than in controls. Cooper et al. (2002) proposed that p19 may be produced by dendritic cells after ligation of TLR2 (603028) with a 19-kd lipoprotein of M. tuberculosis. </p><p>Becher et al. (2002) found that p40 (IL12B) -/- mice showed no clinical evidence of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, after immunization with myelin oligodendrocyte glycoprotein 35-55 (MOG). In contrast, p35 (IL12A) -/- mice were highly susceptible to EAE, with manifestations more severe than in wildtype mice, including severe central nervous system (CNS) inflammation. RT-PCR analysis of CNS-infiltrating cells showed reduced Tnf (191160) and markedly increased Il4 (147780) and Il10 expression in p35 -/- mice compared with wildtype mice. Becher et al. (2002) concluded that p40 is critical for the development of EAE, but the IL12 p70 heterodimer is completely dispensable. They suggested that another molecule using p40, such as IL23, is likely to be involved in EAE pathogenesis. </p><p>IL12 is composed of p35 (IL12A) and p40 (IL12B) subunits, while IL23 is composed of a p19 (IL23A) subunit and the IL12 p40 subunit. Cua et al. (2003) generated mice lacking only IL23 (p19 -/-), only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them with MOG in an EAE model of multiple sclerosis. The p19 -/- mice were generated by completely removing the p19 locus. Mice lacking p19 or p40 were resistant to development of EAE, whereas mice lacking only p35 were at least as susceptible as wildtype mice. Exogenous IL23 delivered into the CNS, but not intravenously, 2 days before expected onset of disease reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in the latter was delayed and disease was less severe. Administration of recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8, also induced intense EAE, suggesting that IL12 promotes the development of Th1 cells, while IL23 is required for subsequent inflammatory events. MOG immunization induced Th1 cells and proinflammatory cytokines in p19 -/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was observed. Flow cytometric and real-time PCR analyses demonstrated the entry of Th1 cells into the CNS in the absence of IL23, without the recruitment of additional T cells or macrophages or the activation of resident microglia. During EAE, IL23R (607562) and IL12RB1 (601604) were coexpressed by inflammatory macrophages, whereas resident microglia expressed only IL12RB1. Although resident microglia and inflammatory macrophages produced IL23, only inflammatory macrophages responded to IL23. In contrast, IL12 was produced primarily by inflammatory macrophages, and both macrophages and microglia had the potential to respond to IL12. Cua et al. (2003) concluded that IL12 promotes the development of naive T cells, while IL23 mediates late-stage inflammation and seems to be necessary for chronic inflammation. In a commentary, Watford and O'Shea (2003) noted that IL12 now has an 'alibi' in the development of autoimmune disease and that previous studies attributing these deleterious effects to IL12 may need reevaluation, including precise determination of the role of each subunit in this family of dimeric cytokines. </p><p>Grabie et al. (2003) studied transgenic mice expressing cardiac myocyte-restricted membrane-bound ovalbumin (OVA), which are tolerant to OVA. They found that adoptively transferred OVA peptide-specific CD8 (see 186910)-positive T cells could infiltrate the hearts of transgenic mice and induce lethal myocarditis only in the presence of vesicular stomatitis virus infection or when the T cells were first stimulated with OVA peptide in vitro in the presence of recombinant IL12. </p><p>Vom Berg et al. (2013) used a syngeneic mouse model for glioblastoma (GB; see 137800) and administered cytokines in the tumor area to overcome the immunosuppressive GB microenvironment. The authors found that Il12, but not Il23, reversed GB-induced immunosuppression and led to tumor clearance in a T cell-dependent manner. To better replicate the human clinical situation, vom Berg et al. (2013) delayed therapy until after GB progression. They found that intratumoral application of Il12 combined with systemic anti-Ctla4 (123890), but not monotherapy with either Il12 or anti-Ctla4, led to tumor eradication even at advanced disease stages. The Il12 and anti-Ctla4 combination treatment acted predominantly on Cd4-positive T cells, causing a drastic reduction in Foxp3-positive Tregs and an increase in effector T cells. Vom Berg et al. (2013) proposed that the combination of intratumoral IL12 and anti-CTLA4 should be tested in clinical trials for treatment of GB and, possibly, other solid tumors. </p>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Merberg et al. (1992)
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</span>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<p class="mim-text-font">
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Becher, B., Durell, B. G., Noelle, R. J.
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<strong>Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12.</strong>
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J. Clin. Invest. 110: 493-497, 2002.
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[PubMed: 12189243]
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[Full Text: https://doi.org/10.1172/JCI15751]
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<p class="mim-text-font">
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Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg, R. S., Vignali, D. A. A.
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<strong>The inhibitory cytokine IL-35 contributes to regulatory T-cell function.</strong>
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Nature 450: 566-569, 2007.
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[PubMed: 18033300]
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[Full Text: https://doi.org/10.1038/nature06306]
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<p class="mim-text-font">
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Cooper, A. M., Kipnis, A., Turner, J., Magram, J., Ferrante, J., Orme, I. M.
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<strong>Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.</strong>
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J. Immun. 168: 1322-1327, 2002.
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[PubMed: 11801672]
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[Full Text: https://doi.org/10.4049/jimmunol.168.3.1322]
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<p class="mim-text-font">
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Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., Sedgwick, J. D.
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<strong>Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.</strong>
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Nature 421: 744-748, 2003.
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[PubMed: 12610626]
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[Full Text: https://doi.org/10.1038/nature01355]
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<li>
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<p class="mim-text-font">
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Devergne, O., Birkenbach, M., Kieff, E.
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<strong>Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin.</strong>
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Proc. Nat. Acad. Sci. 94: 12041-12046, 1997.
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[PubMed: 9342359]
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[Full Text: https://doi.org/10.1073/pnas.94.22.12041]
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Wolf, S. F., Temple, P. A., Kobayashi, M., Young, D., Dicig, M., Lowe, L., Dzialo, R., Fitz, L., Ferenz, C., Hewick, R. M., Kelleher, K., Herrmann, S. H., Clark, S. C., Azzoni, L., Chan, S. H., Trinchieri, G., Perussia, B.
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