Signal transduction pathways in rheumatoid arthrit

2Signaltransductionpathwaysinrheumatoidarthritiswithemphasisonthep38mitogen-activatedproteinkinase(MAPK)pathwayJohannaWestra1PieterCLimburg1,2FromtheDepartmentsof1Rheumatologyand2PathologyandLaboratoryMedicine,UniversityMedicalCenterGroningen,TheNetherlandsChapter214CONTENTS1.Rheumatoidarthritis1.1Pathogenesis1.2Therapy2.SignaltransductionpathwaysinRA2.1MAPKpathways2.1.1ERK1/22.1.2JNK1,2,32.1.3p38MAPKα,β,γ,andδ2.1.4ERK5/BMK12.2NF-κBpathway2.3JAK-STATpathway3.p38MAPKpathway3.1Identification3.2Downstreameffectsofp383.2.1Geneexpression3.2.2PosttranscriptionalregulationofmRNAstability3.3Inactivationbyphosphatases4p38MAPKinhibitors4.1development4.2p38MAPKinhibitorsinanimalmodelsforarthritis4.3p38MAPKinhibitorsinhumanstudies5ConclusionsSignaltransductionpathwaysinRA151.RHEUMATOIDARTHRITISRheumatoidarthritis(RA)isachronicinflammatoryautoimmunedisease,primarilylocatedinthesynovialjoints,leadingtodestructionofthecartilageandboneasaresultofthechronicdiseaseactivity1.RAaffects0.5-1%ofthepopulationintheindustrializedworldistwotothreetimesmorefrequentinwomenthanmenandcanleadtodisabilityandreducedqualityoflife.1.1.PathogenesisThecauseofRAisstillunknown,butbothgeneticandenvironmentalfactorsappeartoplayarole.Theassociationwithcertainhumanleukocyteantigen(HLA)DR4subtypesandRAhasbeenrecognizedforalongtime2,andnowitisfoundthatratherspecificaminoacidsequences,theso-calledsharedepitope(SE)conferthehighestriskfordevelopingRA3.RAischaracterizedbythepresenceofautoantibodies,especiallyrheumatoidfactorsandantibodiestocitrullinatedproteins(anti-CCP)inthemajorityofthepatients.RecentlyinastudyinbloodbankdonorsitwasdemonstratedthatapproximatelyhalfofpatientswithRAhadspecificserologicabnormalities(rheumatoidfactorandanti-CCPantibodies)severalyearsbeforetheonsetofsymptoms4.TheearliesteventsinRAmightinvolveactivationoftheinnateimmunesystem,whichtriggersaT-cellresponsepossiblydirectedtowardscitrullinatedproteins5.InfiltratingT-cellsinthesynovialmembranemay,bycell-cellcontact,andactivationbydifferentcytokines,suchasTNF-α,IFN-γandIL-17,activatemonocytes,macrophagesandsynovialfibroblasts.Thesecellsthanproducepro-inflammatorycytokines,mainlyTNF-α,IL-1andIL-66.Asthediseaseprogressesmultiplecytokinenetworksenterastateofpersistentactivation,triggeringtheproductionofmatrixmetalloproteinases,ultimatelyresultinginirreversibledamageofcartilageandbone7.1.2.TherapyDMARDS(diseasemodifyinganti-rheumaticdrugs)aredrugsthatareintendedtoinhibitboththeinflammatoryanddestructiveprocessesinRA.OftheseDMARDSmethotrexate(MTX)isthemostcommonlyusedandisregardedasthegoldstandardofDMARDtherapy8.AtdosesusedinthetreatmentofRA,MTXislikelytoactviaanumberofintracellularpathways.Upontransportintocells,MTXisconvertedtopolyglutamatedforms,whichpromoteintracellularretention.Thisresultseventuallyininducedreleaseofadenosine,whichhasananti-inflammatoryeffectonneutrophilsandmononuclearcells8;9.MTXmodulatescytokineresponsesatanumberoflevelsandmaypromoteapoptosisofactivatedlymphocytes10.SincefiveyearsanewDMARDhasbecomeavailable,Leflunomide,whichisanactivemetabolitethatinhibitsdihydro-orotate-dehydrogenase,anenzymeinvolvedindenovopyrimidinesynthesis11.Inhibitionofthisenzymeaffectsvarioussignal-transductionmechanisms,thegenerationofcytokines,andcellproliferationandmigration.However,theseDMARDSstillhavelimitedefficacyandmayleadtotoxicityproblems.Thepro-inflammatoryroleofcytokinesandtheinvolvementofdifferentcelltypesledtothedevelopmentoftherapeuticstoselectivelytargetcytokines.ThekeyroleofTNF-αinthepathogenesisofRAwasdiscoveredbothinexperimentalanimalmodelsandinRApatientsbyFeldmann,Mainiandothers12.TherearenowChapter216threedrugsclinicallyavailablefortreatmentthatblocktheactivityofTNF-α:Infliximab(chimaericmonoclonalantibodytohumanTNF),Adalumimab(humanmonoclonalantibodytoTNF)andEtanercept(solubleTNFreceptorconstruct)andonetoblockIL-1activity:Anakinra(IL-1receptorantagonist).TheefficacyandpossibletoxiceffectsofthesenewdrugshavebeenreviewedbyOlsenandStein13.AlthoughTNFblockadehasbeenamajorbreakthroughinthetherapyofRAinthelasttenyears,therearesomedrawbacks.AbouthalfofthepatientsinclinicaltrialsdonotachieveadequateclinicalresponsesexpressedasACR50responses,remissionisrareandthesedrugsalsohavesideeffects,forinstanceincreasedriskoftuberculosis13.Newdrugstoinhibittheproductionandactivityofinflammatorycytokinesmaybefoundininhibitorsofintracellularsignaltransductionpathways14.Thesepathwaysareinvolvedintheprimaryproductionofthesecytokines,aswellasintheresponsesgeneratedbythesecytokines.TNF-αandIL-1induceavarietyofsignaltransductioncascadesthatleadtotheactivationoftranscriptionfactorsandnexttothetranscriptionandtranslationofgenes,codingforinflammatorymediators.ThecascadesthatareimportantinRAandthepotentialinhibitorswillbediscussedbelow.2.SIGNALTRANSDUCTIONPATHWAYSINRAIntracellularsignaltransductionpathwaysareintracellularmechanismsbywhichcellscanreacttoextracellularstimulisuchasstressandinflammatorycytokines.Inshort,intracellularsignaltransductionistheprocessbywhichacellconvertsanextracellularsigna