MacrophagesandNKcellshelpprovideinnateimmunityagainstinfectionbyintracellularparasitesandcommunicatewitheachothertoregulatethisprocess.Whenstimulated,macrophagessecretethecytokineIL-12thatisessentialforactivationofthecytotoxicactivityofnaturalkiller(NK)cells.IL-12stimulatesthisNKcellresponsethroughactivationofaJAK/STATsignalingpathway.BindingofIL-12toitsreceptoronNKcellscausestyrosinephosphorylationandactivationofJAK2andanotherJAKkinase,Tyk2.Tyk2inturnphosphorylatesthetranscriptionfactorSTAT4,whichcanthentranslocatetothenucleustoactivategenes,includingtheexpressionofinterferon-gamma.IFN-gammaandIL-12inducethedifferentiationofTH1helperTcellsthatactivatemacrophagesthroughinterferon-gamma.AkeymodulatorofNKcellactivationbyIL-12isnitricoxide,NO,producedfromargininebytheinducIBLenitricoxidesynthaseNOS2.InactivationoftheNOS2geneinmiceimpairstheinitialinnateresponsetoinfection,includingtheactivationofNKcells.Thisphenotypeissimilartothatofmicelackinginterferon-gammaorIL-12andasimilareffectcanbeproducedbyinhibitingNOS2withL-N6-iminoethyl-lysine(L-NIL)duringinfection,blockingtheactivationofNKcellsbyIL-12.NOproductiondoesnotaffecttheactivationofJAK2byIL-12,butisrequiredforTyk2activity,thedownstreamactivationofSTAT-4andtheproductionofinterferon-gammabyNKcells.TheroleofNOinTyk2activationisnotyetknown,butdoesnotseemtoinvolvechangethephosphorylationstatusofTyk2.Curiously,activationofTcellsbyIL-12doesnotappeartoinvolvedNOproduction,indicatingadistinctmechanismisinvolvedinNKcells.NOalsoplaysaroleasafeedbackinhibitorofIL-12productionbymacrophages,helpingtopreventover-activationoftheTh1cellsbyIL-12.NOappearstomakeanimportantcontributiontotheearlyinnateresponsetoinfectionsbeforespecificimmunityisactive.

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