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

REFERENCES:Kaplan,M.H.,Sun,Y.L.,Hoey,T.,Grusby,M.J.(1996)ImpairedIL-12responsesandenhanceddevelopmentofTh2cellsinStat4-deficientmice.Nature382(6587),174-7Mullen,A.C.,etal.(2001)RoleofT-betincommitmentofTH1cellsbeforeIL-12-dependentselection.Science292(5523),1907-10Ouyang,W.etal.(1999)TheEtstranscriptionfactorERMisTh1-specificandinducedbyIL-12throughaStat4-dependentpathway.ProcNatlAcadSciUSA96(7),3888-93Thierfelder,W.E.etal.(1996)RequirementforStat4ininterleukin-12-mediatedresponsesofnaturalkillerandTcells.Nature382(6587),171-4Visconti,R.etal.(2000)ImportanceoftheMKK6/p38pathwayforinterleukin-12-inducedSTAT4serinephosphorylationandtranscriptionalactivity.Blood96(5),1844-52

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