Interleukin-12(IL-12)promotescell-mediatedimmunitybyinducingTh1celldifferentiationandactivationofbothTcellsandNKcells.DendriticcellsandmacrophagesinperipheraltissuesactasantigenpresentingcellsandsecreteIL-12asonecomponentoftheantigenresponse,Th1differentiation.TheroleofIL-12incellularimmunityislargelymediatedbytheSTAT-4transcriptionfactor.STAT-4isessentialforIL-12activityandthephenotypeofmicelackingSTAT-4isverysimilartothephenotypeofmicelackingtheIL-12receptororIL-12.TheroleofIL-12inTh1differentiationmaynotbetoinducetheTh1cellfate,buttostimulategrowthofcellsdeterminedfortheTh1cellfatebytheT-bettranscriptionfactor.SeveralsignalingpathwayscontributetoIL-12activationofSTAT-4toregulatecell-mediatedimmuneresponses.TheJAKkinasessuchasJAK2andTYK2interactwiththeactivatedIL-12receptorandtyrosinephosphorylatetheIL-12receptorandSTAT-4.IL-12alsoactivatesamapkinasepathwayactivatingthemapkinasekinaseMKK6andp38.PhosphorylationofSTAT-4onserine721byp38contributestothefulltranscriptionalactivationofgenesbySTAT-4.SomeoftheeventsdownstreamofIL-12appeartoincludegenesactivatedindirectlybySTAT-4,suchasgenesactivatedbythetranscriptionfactorERM.ERMisintheEtsfamilyoftranscriptionfactors,isactivatedbyIL-12andactivatesIL-12inducIBLegenessuchasInterferon-gammathatarenotactivatedbySTAT-4itself.Interferon-gammatranscriptioninTcellsisalsoactivatedbyothersignalssuchasfromtheTcellreceptor.OtherproteinsactivatedtranscriptionallydownstreamofIL-12andSTAT-4includethechemokinereceptorCCR5andIL-18anditsreceptor.Someviruses,includingHIV,represscell-mediatedimmunitybyblockingIL-12signaling.

Contributor:GlennCroston,PhD

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