NewInsightsintotheAnti-inflammatoryMechanismsofGlucocorticoids:AnEmergingRolefor
Glucocorticoid-Receptor-MediatedTransactivation
SofieVandevyver,LienDejager,JanTuckermann,andClaudeLibert
DepartmentforMolecularBiomedicalResearch(S.V.,L.D.,C.L.),FlandersInstituteforBiotechnology,andDepartmentofBiomedicalMolecularBiology(S.V.,L.D.,C.L.),B9052Ghent,Belgium;andInstituteforGeneralZoologyandEndocrinology(J.T.),UniversityofUlm,D-89081Ulm,Germany
Glucocorticoidsareanti-inflammatorydrugsthatarewidelyusedforthetreatmentofnumerous(autoimmune)inflammatorydiseases.Theyexerttheiractionsbybindingtotheglucocorticoidreceptor(GR),amemberofthenuclearreceptorfamilyoftranscriptionfactors.Uponligandbinding,theGRtranslocatestothenucleus,whereitactseitherasahomodimerictranscriptionfactorthatbindsglucocorticoidresponseelements(GREs)inpromoterregionsofglucocorticoid(GC)-induciblegenes,orasamonomericproteinthatcooperateswithothertranscriptionfactorstoaffecttranscription.Fordecades,ithasgenerallybeenbelievedthattheundesirablesideeffectsofGCtherapyareinducedbydimer-mediatedtransactivation,whereasitsbeneficialanti-inflam-matoryeffectsaremainlyduetothemonomer-mediatedtransrepressiveactionsofGR.Therefore,currentresearchisfocusedonthedevelopmentofdissociatedcompoundsthatexertonlytheGRmonomer-dependentactions.However,manyrecentreportsunderminethisdogmabyclearlyshowingthatGRdimer-dependenttransactivationisessentialintheanti-inflammatoryactivitiesofGR.ManyofthesestudiesusedGRdim/dimmutantmice,whichshowreducedGRdimerizationandhencecannotcontrolinflammationinseveraldiseasemodels.Here,wereviewtheimportanceofGRdimersintheanti-inflammatoryactionsofGCs/GR,andhencewequestionthecentraldogma.WesummarizethecontributionofvariousGRdimer-inducibleanti-inflammatorygenesandques-tiontheuseofselectiveGRagonistsastherapeuticagents.(Endocrinology154:993–1007,2013)
lucocorticoids(GCs)arecriticalregulatorsofawidevarietyoffundamentalprocesses,includingmeta-bolichomeostasis,cellproliferation,inflammatoryandimmuneresponses,development,andreproduction(1–3).Atpharmacologicconcentrations,GCsdisplaypotentan-ti-inflammatoryeffects.Hence,numerousautoimmune,inflammatory,andallergicdisorders,suchasasthma,rheumatoidarthritis,ulcerativecolitis,andallergicrhini-tis(4,5),areoftentreatedwithsyntheticGCs,suchasdexamethasoneandprednisolone.Despitetheirexcellentanti-inflammatoryefficacy,theuseofGCsastherapeuticsisoftenrestrainedduetotwomajordrawbacks.First,long-termtreatmentwithGCsisoftenaccompaniedby
ISSNPrint0013-7227ISSNOnline1945-7170PrintedinU.S.A.
Copyright©2013byTheEndocrineSociety
doi:10.1210/en.2012-2045ReceivedOctober12,2012.AcceptedJanuary4,2013.FirstPublishedOnlineFebruary5,2013
G
severesideeffects,suchasdiabetes,osteoporosis,hyper-tension,andmuscleatrophy(6,7).Second,theoccurrenceofGCresistancealsolimitsthesuccessofmanyGC-basedtherapies.
GCsexerttheirfunctionsbybindingtotheirintracel-lularreceptor,theglucocorticoidreceptor(GR),whichisaligand-inducibletranscriptionfactorbelongingtothenuclearreceptorsuperfamily(8).TheGRisamodularproteincomposedofthreemajorfunctionaldomains:theN-terminaldomain,thecentralDNA-bindingdomain(DBD),andtheC-terminalligand-bindingdomain(LBD).TheDBDconsistsoftwozincfingersimportantforGRdimerization,nucleartranslocation,andDNAbinding.
Abbreviations:AIA,antigen-inducedarthritis;AP-1,activatorprotein1;CIA,collagen-inducedarthritis;COX2,cyclooxygenase2;DBD,DNA-bindingdomain;DNBS,dini-trobenzenesulfonicacid;GC,glucocorticoid;GILZ,GC-inducedleucinezipper;GR,glucocorticoidreceptor;GRE,GRresponseelement;JNK,c-junN-terminalkinase;LBD,ligand-bindingdomain;LPS,lipopolysaccharide;MR,mineralocorticoidreceptor;NF-B,nuclearfactor-B;nGRE,negativeGRE;SEGRAs,selectiveGRagonists;TA,transactivation;TR,transrepression.
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994VandevyveretalAnti-inflammatoryPotentialofGRDimersEndocrinology,March2013,154(3):993–1007
adrenalglandinacircadianrhythmandundergopulsatilesecretion(22–24).
AlthoughinactiveGRisfoundprimarilyinthecytoplasm,itisnotrigidlycompartmentalized.GRshuttlescontinuouslybetweenthenucleusandthecytoplasmthroughthenuclearporechannel(reviewedinRef.15).Nevertheless,uponligandbinding,GRundergoesconformationalchangesandismainlyfoundinthenucleusduetoitsligand-inducednucleartranslocation.Inthenucleus,GRmediatestheup-regulationofnu-merousgenesanddown-regulationofothersinacoordinatedfashion.
Figure1.GeneralStructureoftheGRGR(human)iscomposedofanN-terminaldomain(NTD),
PositiveregulationisoftenmediatedaDBD,ahingeregion,andaC-terminalLBD.TheGRDBDcontainstwozincfingersinwhichthe
bythebindingofGRtoGR-bindingzincmoleculeislocatedbetweenfourcysteineresidues.InGRdim/dimmiceA458(red)ismutated
toathreonine.ThemutantGRcannotformdimers.sites.Thebest-describedmechanism
oftranscriptionalactivationisthedi-rectbindingofGRhomodimersto
Eachzincfingercontainsazincatombetweenfourcys-so-calledGRresponseelements(GREs)inthepromoter
teineresidues.Thesecondzincfingerismoreimportant
regionsofGC-induciblegenes(25).Infact,GRho-forGRdimerization.TheDBDandLBDarelinkedbya
modimerscanbindinthemajorgrooveofDNAviatheir
hingeregion,whichallowsnucleartranslocationofGR
DBD-containingtwozincfingersandthustargetaGRE
(9–11)(Figure1,upperpanel).Additionally,GCscanalso
(5,26).TheconsensusGREsequenceisaninvertedim-bindtoanothernuclearreceptor,themineralocorticoid
perfecthexamericpalindromeseparatedbyaspacerof3
receptor(MR),witha10-foldhigheraffinitythanwith
bp(5Ј-AGAACAnnnTGTTCT-3Ј,inwhich“n”isanynu-GR(12),butinterferenceofGCsinMRsignalingislimitedcleotide)(5,27).ThesequenceoftheGREvariesamongduetothetopicalrestrictionofMRexpression.Whereasdifferentpromoters,andthereforetheGREcanbecon-GRiswidelyexpressed,MRisexpressedonlyincertainsideredasasequence-specificallostericliganddirectingtypesofcells(andregulatessaltandwaterhomeostasis).thetranscriptionalactivityofGR(28,29).However,re-Furthermore,theactionofGCsthroughtheMRislimitedcentglobalChIP-SeqdatarevealthatGRbindstoDNAbytheactivityof11-hydroxysteroiddehydrogenase2inmostlyviatheGREconsensusmotif(30).Additionally,cellsinwhichMRisexpressed(13,14).nexttotransactivation(TA)of“simple”GREmotifsbyInitsinactivestate,GRresidespredominantlyintheGRdimers,GRcancooperatewithothertranscriptioncytoplasm,whereitissequesteredinamultimericchap-factorsasamonomericproteintoinducetranscriptioneronecomplexconsistingofheatshockproteins(suchas(31,32)toso-called“composite”elementsorbya“teth-hsp90,hsp70,hsp90bindingproteinp23),immunophi-ering”mechanism.BindingofGRtoDNAleadstore-lins(eg,FKBP51,FKBP52,Cyp44,andPP5),andothercruitmentofdistinctcofactorsthatenablechromatinre-factorstopreventitsdegradationandtoassistinitsmat-modeling,RNApolymeraseIIbinding,andsubsequenturation(15–17).TheGRisconstitutivelyexpressedingeneinduction.ThemechanismsofGR-mediatedtran-virtuallyallcelltypes,butthedifferenttissue-specificpat-scriptionalrepressionortransrepression(TR),ontheternsleadtotissue-specificoutcomesindifferentdiseasesotherhand,aremorepromiscuousandpartlyinvolve(18,19).Furthermore,GR-mediatedeffectsarereadilyDNAbindingofhomodimericGRtosimplenegativeinfluencedbyepigeneticregulators,context,andotherun-GREs(nGREs)orinvertedrepeats(IR)withlessthanthreerecognizeddeterminants(20,21).Inaddition,thekeyspacerstospecificallyrepressgenetranscription(33–35).variablesthatdeterminetheGR-mediatedoutcomein-Furthermore,GC-activatedmonomericGRcannega-cludetimingandgenomicaccessibilityofGC-responsivetivelyregulategenetranscription,eg,bytetheringothergenes.Thenatureandmagnitudeofacell’sresponsetotranscriptionfactors,suchasnuclearfactor-B(NF-B)GCsalsodependonthelevelsofhormonessecretedbytheandactivatorprotein1(AP-1),orthroughcross-talkwith
Endocrinology,March2013,154(3):993–1007endo.endojournals.org995
CurrentConceptoftheAnti-inflammatoryMechanismofGC/GR:EmphasisonTR
Untilrecently,itwasgenerallybe-lievedthatTRoftranscriptionfac-torsbymonomericGRisthemaindeterminantoftheanti-inflamma-torypropertiesofGR,whereasitssideeffectsresideinitsTApotential(36,38,39,46).Thisconcepthasbeenreviewedextensively(31,41,47).Briefly,itisknownthatTA,throughdirectDNAbinding,in-ducestheexpressionofseveralen-zymes(eg,phosphoenolpyruvatecarboxykinase,tyrosineaminotransfer-ase,andglucose6-phosphate)involvedinglucoseandlipidmetabolism.Hence,uncontrolledup-regulationofthesegenescouldaccountforthediabetogeniceffectsofGCs,which
Figure2.GRSignalingActivatedGRcanleadtoeitheractivationorrepressionofgeneresultinhyperglycemiaandde-transcription.Leftgreenpanel:TAismediatedby(i)bindingofGRdimerstoGRE,(ii)DNA
creasedcarbohydratetolerance(1,
bindingofGRinconcertwithanothertranscriptionfactor(TF:XY),or(iii)bindingofGRtoaTF
48).Ontheotherhand,itisbelievedbyatetheringmechanism.Rightredpanel:TRismainlyachievedby(iv)directbindingofGR
dimerstonGRE(simpleorIR),(v)DNA-bindingcross-talkwithanotherTF,(vi)interferenceofthattheanti-inflammatoryactionsmonomericGRwiththeTAactivityofTFsbyatetheringmechanism,(vii)competitionforanofGCtherapyarepredominantlyre-overlappingbindingsite(competitiveGRE),(viii)sequestrationofaDNA-boundTF,or(ix)
latedtotheTReffectsofGR(11,49)competitionforbindingcofactorswithotherDNA-boundTFs.
becausesomeinflammatorypro-cessescouldstillberestrictedinadim/dimothertranscriptionfactorsandbindingto“composite”mousestrain(GR)inwhichGRislargelydimeriza-elements(36,37).Foranoverviewofthefundamentaltiondefectiveduetoreplacementofanalaninebyathre-aspectsofGRtranscriptionalregulation,seeFigure2.onine(A458T)(11,50,51).Thismutationislocatedinthe
Theanti-inflammatoryeffectsofGRarebelievedtosecondzincfingerintheDBDofGR(Figure1,lowergenerallyresultfromtetheringprotein-proteininterac-panel)andcausesreducedbindingtoDNAand,moretionsbetweenGRandothertranscriptionfactors,partic-specifically,totheGRE(11,50,51).
TRofinflammatorytargetgenesmostofteninvolvesularlyNF-BandAP-1,whichresultsinTRofawide
varietyofproinflammatorygenes.Ontheotherhand,theinterferenceofGRwiththeactivityofDNA-boundpro-debilitatingGC-mediatedeffectsarethoughttobecausedinflammatorytranscriptionfactors,suchasNF-B,cAMP
responseelement-bindingprotein,interferonregulating
byTAofsimpleGREgenes(38,39).Accordingly,so-factor-3,nuclearfactorofactivatedTcells,signaltrans-calledselectiveGRagonists(SEGRAs)thatfavorTRwere
ducersandactivatorsoftranscription,Th1-specificTbox
developedastherapeuticagentswithreducedsideeffects.
transcriptionfactor,GATA3,andAP-1(52–54).Because
ExamplesareRU24858,compoundA,AL-438,LGD5552,
thesetranscriptionfactorsregulatetheexpressionofin-andZK216348(40–45).However,morerecentdataflammatorygenes,GR-mediatedtetheringofthesetran-showthattheTApotentialofGRisindispensableforitsscriptionfactorseventuallyleadstorepressionofalargeanti-inflammatoryproperties,atleastincertaindiseasenumberofproinflammatorymediators:cytokines(includ-settings.Here,weprovideanoverviewoftheanti-inflam-ingTNF,granulocytemacrophagecolonystimulatingfac-matorymechanismsofGR,focusingmainlyontheinduc-tor,IL-1,IL-2,IL-3,andIL-6),chemokines(eg,eotaxin,tionofanti-inflammatorygenesbyGRasahomodimericmacrophageinflammatoryprotein[MIP],andregulatedtranscriptionfactorandwithemphasisoninvivostudies.andnormalTcellexpressedandsecreted[RANTES]),en-
996VandevyveretalAnti-inflammatoryPotentialofGRDimerszymes(suchasinduciblenitricoxidesynthaseandcyclo-oxygenase2[COX2]),andadhesionmolecules(eg,inter-cellularadhesionmolecule1andvascularcelladhesionmolecule1).Thus,negativeregulationbytetheringhasbecomeaparadigmfortheanti-inflammatoryandim-mune-suppressiveactionsofGR.Themost-studiedcross-talkmechanismsarethosebetweenGRandNF-B,GRandAP-1,andGRandinterferonregulatingfactor-3(41,42,45,55).
StudiesonGRdim/dimMice:TheEmergingRoleofGRDimerizationintheAnti-inflammatoryFunctionofGR
Asmentionedabove,moststudiesclaimthatinteractionofmonomericGRwithproinflammatorytranscriptionfac-torsisthebasisofitsanti-inflammatoryactivity.How-ever,thecontributionofGRdimerstoitsanti-inflamma-torypropertyremainscontroversial.MountingevidenceindicatesthattheTApotentialofGRdimersisrequiredforexecutionofthecompleteanti-inflammatorycascade(49,56–59).MoststudiesinvolvedexperimentsinGRdim/dimmice.
Importantly,GRE-dependentgenetranscriptionisdi-minishedincellsoriginatingfromGRdim/dimmice,asshownbyimpairedinductionofamousemammarytumorvirus-CATreporterinGRdim/dimmouseembryofibroblastcellsandGR-induciblegluconeogenicenzymes,suchasg6pandpck1,inliverlysatesofGRdim/dimmiceandre-duced(butnotabsent)GCregulationofgenesintheliverasrevealedbygenome-wideexpressionprofiling(10,11).However,therepressingfunction(cross-talkwithAP-1andNF-B)ofGRisstillintactinGRdim/dimmice(11,49,51,60).
Almostallevidencediscussedinthisreviewisbasedontheanalysisofthesingle-pointmutantA458T,otherwiseknownastheGRdim/dimmutant.However,oneshouldconsiderthesedatawithcaution,becausemountingevi-denceindicatesthatadditionalresiduesareindispensableforGRdimerization.TheideathatGRdim/dimmutantscannotformdimershasbeenchallengedbyarecentstudy(61).Humanosteosarcoma(U-2OS)cellsexpressingtheGRwt/wtreceptororthehGRdim/dim(A458T)orhGRdim4(A458T,R460D,D462C,andN454D)mutantwereusedwithGRE-drivenreportersintransientreportergeneas-says.TheresultsrevealedthatthehGRdim4mutantisevenmoreunresponsivetosteroidsthanthehGRdim/dim(A458T)mutant.ThesefindingsareinagreementwiththeresistanceofhumancelllinescarryingthesemutationstoGC-mediatedapoptosis(61).ThesefindingsareinlinewithearlierpublisheddatashowingthatboththeGRdim/dimEndocrinology,March2013,154(3):993–1007
andGRdim4mutationsintheD-loopstronglyinhibitedGRdimerizationandGR-mediatedTAbutdidnothampertherepressionofAP-1andNF-B(51).Indeed,Jewelletal.(61)alsoshowedthattheTRcapacityofhGRdim/dimwasindeedunaffected.Whatisparticularlyinterestingisthatimmunoprecipitationexperimentsshowedthatboththehuman(h)GRdim/dimandhGRdim4receptorscouldpromptlyformdimers.Ofcourse,thesestrikingfindingsshouldbeexperimentallyconfirmedfurther.Further-more,Savoryetal.(62)havedemonstratedanoveldimerinterfaceintheLBDofGR.Mutatingthisdimerinterface’smostimportantresidues(P625andI628)toalaninesre-sultedina10-folddecreaseindimerizationaffinityrela-tivetowild-type(WT)LBD.Furthermore,byusingamousemammarytumorvirusreporterassay,Bledsoeetal.(63)showedthattheresiduesofthisdimerinterfacearealsoimportantfortheGRTAfunction,.Inaddition,morerecentgeneexpressionprofilingbyFrijters(10unambig-uouslyconfirmsthattheGRdim/dimmutantcanstilltrans-activatesomegenes,albeitnotasstronglyasitswildtypecounterpart.
Takentogether,alltheabove-mentionedfindingsindi-catethatthesingle-pointmutationintheDBD,namelyA458TintheGRdim/dimmutant,maynotbesufficienttocompletelyabolishdimerizationandthusGR-mediatedTA.Mostprobably,theGRdim/dimmutantcanstillbindtoasetofGR-responsivepromoters,althoughinacelltype-andgenepromoter-specificmanner,byformingmultim-ersindependentlyoftheDBD-dimerinterface.Neverthe-less,allstudiesperformedwiththeGRdim/dimmutantandsubsequentfindingsdoprovethatthissingle-pointmuta-tionreducesdimerization,andthattheGR-DNAbindingpotentialandTAarecriticallyimportantintheanti-in-flammatoryactionsofGR.
MicecarryingtheGRdim/dimmutation(11)areviable,incontrasttothefullGRknock-outmouse(64).GRdim/dimmicearenormalinsizeandappearnormal,buttheydoshowsomeanomalies,suchasincreasedexpressionofPomcinthepituitarygland,whichdemonstratesthelossofnegativecontrolofPomctranscriptionbyGRdimers.ThisresultsinelevatedlevelsofsecretedACTHandGCs(11,65).Additionally,studiesonGRdim/dimmicerevealedthatGRdimerizationisrequiredforGC-mediatedthy-mocyteapoptosisandlong-termproliferationoferythro-blasts(11).Anothercellularprocessthatnecessitatesac-tionofGRdimersisadipogenesis:thisprocesscouldbepromotedbyinductionofKrüppel-likefactor15byadimerizedGR(66).Furthermore,GRdimersarealsore-quiredforthetask-relatedfacilitatingeffectsofGCsonspatialmemory(65).Incontrast,dimerizationofGRisdispensableforepidermalandhairfollicledevelopmentduringembryogenesis(67).
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Table1.
IdentificationoftheroleofGRdimersindifferentphysiologicalresponsestoGCsbyusingGRdim/dimmice
Effects
GRDimerizationRequiredRequiredRequiredDispensableRequiredRequiredDispensableDispensableRequiredRequiredRequiredDispensableRequiredRequired
ImportantCellTypesIL-17producingT-cellsMacrophagesNeutrophilsMacrophages
T-lymphocytesMacrophagesIntestinalepithelialcellsEnterocytes
OsteoblastsOsteoclastsUnknownUnknownFibroblastsThymocytesUnknownErythroblastsUnknown
References(56)(58)(57)(49,60)(59)(124)(85,125)(126)(123)(66)(11,61)(67)(11)(65)
Resolutionofinflammation
Antigen-andG6PI-inducedarthritisContacthypersensititivity
LPS-andCLP-inducedsepticshock
PMA-inducedirritativeskininflammationTNF-inducedinflammationSideeffects
HyperglycemiaOsteoporosis
SkeletalmuscleatrophyWoundrepairCellularprocessesAdipogenesisApoptosis
EpidermaldevelopmentduringembryogenesisProliferationSpatialmemory
CLP,cecalligationandpuncture;PMA,phorbolmyristateacetate.
ThecontributionoftheDNA-bindingfunctionofGRtotheanti-inflammatoryeffectsofGRwasuntilrecentlystronglyunderestimated.SeveralstudieshaveexploitedtheresponseofGRdim/dimmiceinseveralinflammatorydiseasemodels(Table1).IthasbeenshownthatDNA-bindingGRdimersarenotrequiredinGCtherapyofirritativeskininflammationinducedbyphorbolester(phorbolmyristateacetate),andthatGRmonomerscaninhibitinflammationinthismodel(49,60).Incontrast,GRdim/dimmicewererefractorytoGCtreatmentinamousemodelofcontacthypersensitivity,whichmimicsallergiccontactdermatitis(58).ThesedataindicatethatdimerizationofGRandsubsequentGRE-dependenttran-scriptionareindispensablefortherestrictionofcertainallergicinflammatorydisorders.Similartocontacthyper-sensitivity,Baschantetal.(56)showedthatGCsrequireGRdimeractivitytorestraininflammationintwomurinerheumatoidarthritismodels:antigen-inducedarthritis(AIA)andglucose-6-phosphateisomerase-inducedarthri-tis.GCtreatmentdidnotprotectGRdim/dimmice,indicat-ingthattheDNA-bindingcapacityofdimericGRisrequiredforGC-mediatedsuppressionofarthritisinflam-mation.Moreover,GRdim/dimmicearealsohighlysuscep-tibleinseveralsepticshockmodels,suchassepsisinducedbylipopolysaccharide(LPS)orcecalligationandpunc-ture,andinflammationinducedbyTNF(57,59).Thesestudiesprovideevidencethatinsepticshock,thethera-peuticactionsofendogenousandexogenousappliedGCsrequireGRdimerization.Takentogether,thesedataun-derminetheconceptthatGRmonomersareresponsibleformostoftheanti-inflammatorypotentialofGCsandclearlyshowthatGRdimer-dependentTAisessentialfortheanti-inflammatoryactivitiesofGR.
GRDimer-DependentTranscriptionalActions
GR-mediatedTAofanti-inflammatorygenes
GeneexpressionprofilingofliversofGRwt/wtandGRdim/dimmicetreatedwithprednisolonerevealedthatmanygenescouldnotbesignificantlyinducedinGRdim/dimmice,indicatingthattheirinductiondependsonGRdimers(10).Manyofthesegeneshavewell-knownanti-inflammatoryactionsand,hence,mightcontributetotheanti-inflammatorypropertiesofGR.Here,wewillfocusonafewprominentgenesandelaborateontheiranti-inflammatoryactions.AcompleteoverviewofallGC-inducibleanti-inflammatorygenesidentifiedsofarandtheireffectsontheproinflammatorycascadearedepictedinTable2andFigure3.
WhereasDusp1,Tsc22d3,andAnxa1areonlyjustafewGC-induciblegenesmediatingsomeoftheanti-in-flammatorycapacitiesofGR,microarrayprofilingdataindicatethatmanyothergenesarepositivelyregulatedbyGRandplayaputativeroleinthedisputeagainstinflam-mation(10,57,68).However,identificationofthesegenesandtheirfunctionalityisstillinitsinfancy,whichmeansthatthecomplexityoftheanti-inflammatoryna-tureofGRisstillfarfromfullyunderstood.
MAPKphosphatase1ordualspecificityphosphatase1(MKP-1orDusp1)
Dualspecificityphosphatase1(encodedbyDusp1)isoneofthemostpotentanti-inflammatoryGR-inducibleproteins.Itisamemberofthedual-specificityphospha-tases,whichinclude10members,andcatalyzesthede-phosphorylationandsubsequentinactivationofboth
998VandevyveretalAnti-inflammatoryPotentialofGRDimersEndocrinology,March2013,154(3):993–1007
Table2.
SymbolADORA3ADRB1ANPEP
ListofGC-InducedAnti-inflammatoryGenes
Description
AdenosineA3receptor2-Adrenergicreceptor1AminopeptidaseN
Anti-inflammatoryMechanism
References(68)(128)(129)(99–103)(130–132)(133–139)(68,140–143)(68)(144)
(145–148)(149)(59,71–75)(68)
(150,151)(68)
(68,152,153)(154,155)(156)
(46,50,157,158)(159)(68)(160)
(161,162)(163)(160)(160)(164)(165)(82–84,86–90)(137,
166–171)
Inhibitionofeosinophilchemotaxis
SuppressionofJNKsignaling,suppressionofcytokinesecretionCleavesantigenpeptidesboundtomajorhistocompatibilitycomplexclassIImoleculesofpresentingcells
ANXA1Annexin-1Inhibitionofphospholipase2(cPLA2),COX-2andNF-BASBT/SLC10a2Apicalsodium-dependentbileBileacidtransporter
acidtransporter
CC10Claracell10kDaInhibitionofphospholipase2(cPLA2);bindshydrophobic
ligands,eg,phospholipidsandprostaglandins;inhibits
chemotaxisandphagocytosisofneutrophilsandmonocytes
CD163HemoglobinscavengerClearanceofproinflammatoryhemoglobin-haptoglobin
receptorcomplexes
CD1dAntigen-presentingMHCI-mediatedimmunosuppression(stimulatesinhibitoryNK
glycoproteinandinvariantT-cells)
CYP1A2Thymosinand4sulfoxideInhibitsneutrophilchemotaxis
DEXRAS1/AGS-1RAS,dexamethasone-inducedInhibitsligand-dependentsignalingbytheGi-coupledFPRand
1subsequentlyERK-1/2activation;blocksPKCkinaseactivity
DOK-1Dockingprotein1Inhibitoryadaptorprotein(suppressesactivationofMAPK
cascade)
DUSP1/MKP-1Dualspecificityphosphatase1InhibitsMAPKs(JNK/p38/ERK)FCARReceptorforFcfragmentofInteractswithIgA-opsonizedtargets
IgA
FOXP3ForkheadboxP3SuppressionofTregcellsFPRFormylpeptidereceptorSuppressionofcytokinesecretionIL-10IL-10SuppressionofTregcells,inhibitsexpressionof
proinflammatorycytokines,inhibitsNF-Bactivation
IL-1r2IL-1receptortypeIIDecoyreceptorforIL-1receptorIL-1raIL-1receptorantagonistCompetitiveinhibitionofIL-1bbindingtoitsreceptorIB␣InhibitorofNF-BInhibitionofNF-BKLF2LILRB1MT1X
p11/S100A10p57Kip2PAI-1RGS-2SLAPSLPI
TSC22D3/GILZTTP
Kruppel-likefactor2
Leukocyteimmunoglobulin-likereceptor,subfamilyBmember1
Methallothionein1X
S100calciumbindingproteinA10
Cyclin-dependentkinaseinhibitor1C
Plasminogenactivatorinhibitor1
RegulatorofG-proteinsignaling2
Src-like-adaptorprotein
Secretoryleukocytepeptidaseinhibitor
TSC22domainfamily,member3Tristetraprolin
InhibitionofNF-BandAP-1
MHCI-mediatedimmunosuppressionFreeradicalscavenger
Inhibitionofphospholipase2(cPLA2)Cyclin-dependentkinaseinhibitorInhibitionofthefibrinolyticcascadeReducesGq-linkedsignaling
ReducesT-cellsignalingbyinteractingwithSyk/Zap70Inhibitorofserineproteases
InhibitionofNF-B,AP-1,Raf-1andRasDestabilizesmRNAandincreasesmRNAturnover
PKC,proteinkinaseC.
threonineandtyrosineresiduesinMAPKs,hencethenameMAPKphosphatases(MKPs)(69,70).Therearethreewell-definedMAPKsubfamilies:theERKs,c-JunN-terminalorstress-activatedproteinkinases(c-junN-terminalkinase[JNK]orstress-activatedproteinkinase),andp38MAPK.Thesekinasesplayanintricateroleinthehost-immuneresponseleadingtotheactivationofproin-flammatorytranscriptionfactors,suchasNF-BandAP-1,andensuingactivationofvariouscytokines,chemo-kines,andinflammatorymediators.MKP-1wasorigi-nallyidentifiedasaphosphatasespecificforERKMAPKs(71,72).However,consecutivestudieshaveshownthat
Endocrinology,March2013,154(3):993–1007endo.endojournals.org999
Figure3.AnOverviewofAllKnownGC-InducibleAnti-inflammatoryGenesandTheirEffectsontheProinflammatoryCascade.GRcanresolveinflammationby(i)hamperingtheactivationofproinflammatorysignalingpathwaysthroughinductionofIL-1receptorantagonist(IL-1ra),IL-1rtypeII(IL-1r2),secretoryleukocytepeptidaseinhibitor(Slpi),thymosin4sulfoxide,adenosineA3receptor(ADORA)andaminopeptidaseN(ANPEP);(ii)interferingwithsignalingcascadesthroughDok-1,SLAP,Dexras-1,RGS-2,Gilzandp57Kip2;(iii)inhibitionofsubsequentMAPKactivationviaGilz,MKP-1,p57Kip2andB2adrenoceptor;(iv)interactingofGilz,IB␣,Annexin-1,KLF2andIL-10withproinflammatory
transcriptionfactors;(v)inducingmRNAdestabilizationthroughTTP;(vi)inhibitingproteinfunctionviainductionofAnnexin-1,Cc10,IL-10,p11,p57Kip2,FPR,CD1d,LILRB1,Foxp3andMT1X;(vii)negativelyregulatingvariousprocessesthroughANPEP,PAI-1,Foxp3,B2adrenoceptor,Cc10,ASBT,LILRB1,FCARandCD163.
MKP-1hasapreferenceforJNKandp38MAPKs(73–75).TheinteractionofMKP-1withitssubstrates,theMAPKs,increasesitsactivityupto6-to8-fold(76).TheregulationofMkp1isofmuchinterestbutremainscontro-versial.Recently,ChIPsequencingrevealedaGREsiteinthepromoterregionofMkp1(77,78).Moreover,itwasshownthattheGC-mediatedinductionofMkp1isdependentonGRdimerizationwhencellsandtissuesareexposedtoGCsaloneorincombinationwithTNF(10,59),whereasMKP-1proteinissimilarlyinducedinGC-pretreatedcellsfollowedbyLPSinduction(79).Mkp1isexpressedinresponsetoGCsinawidevarietyoftissues,butitcanalsobeinducedbyseveralproinflammatorystimuli,suggestingthatMKP-1functionsasanegativefeedbackregulatorofMAPKsignal-ingandisconsequentlycriticalfortheresolutionofinflam-mation.MKP-1wasalsosuggestedtomediatetheprotectiveroleofendogenousGCsbyinterferingwithp38signalingduringLPS-inducedsepticshock(80).Knowledgeoftheim-portanceofMKP-1inthecombatagainstinflammationwasgainedfromstudiesonMkp1Ϫ/Ϫmice(foranoverviewofthe
useofMkp1Ϫ/ϪmiceinproinflammatorydiseasemodelsseeTable3).Additionally,anincreasingnumberofinvivostud-iesmakinguseofMkp1Ϫ/ϪmicedemonstratethatMKP-1contributestotheanti-inflammatoryresponsesofGCs.Forexample,GCscanprotectMkp1Ϫ/Ϫmiceonlypartlyagainstendotoxicshock(81)andTNF-inducedinflammatoryshock(59).Mechanistically,MKP-1protectsagainstTNF-inducedlethalshockbydephosphorylatingJNK,morespecificallyJNK-2(59).Furthermore,itwasshownthatdimerizationofGRisessentialforprotectionagainstacuteTNF-mediatedinflammationandcriticalforMkp1inductionandhencecontrolsactivationoftheproapoptoticJNK-2.Inthisrespect,thisstudywasthefirsttoprovethatGRdimerizationisalsoimportantintheregulationofTNF-inducedapoptosis(59).
ThesefindingstogethershowunambiguouslythatMKP-1hasapivotalroleasanegativefeedbackregu-latoroftheMAPK-signalingcascadeandhenceisim-portantinproinflammatorycytokineproductionandinnateimmunity.
1000VandevyveretalAnti-inflammatoryPotentialofGRDimersEndocrinology,March2013,154(3):993–1007
Table3.
UseofMkp1Ϫ/ϪMiceinSeveralDiseaseModels
Anti-inflammatory
MechanismInhibitionofp38InhibitionofMAPKInhibitionofJNKDeficiencyinCD4ϩTcellsroleforJNK?Inhibitionofp38Inhibitionofp38Inhibitionofp38Inhibitionofp38andJNKInhibitionofp38andJNK
Outcome
Enhancedmastcelldegranulation;increasedhypothermia
Severecolitis,mucosalhyperplasiaResistantResistant
Increasedcytokinelevels;increasedjoint-swelling;inflammationinankleandwristjoints
Inflammatoryboneloss
LowerlevelsofeNOSandlowerNO
production;increasedlevelsofarginaseI/IIImpairedbacterialclearance;increasedcytokinelevels;infiltrationofneutrophilsinlungs;increasedmortality
Increasedcytokineandchemokinelevels;greaterNOproduction;neutrophil
infiltration;severeorgandamage;highermortality
Increasedweightloss;impairedviralclearance
Greaterinfarctinjury
Increasedcytokinelevels;hypotension;respiratoryfailure;increasedNO
production;MOF;increasedmortalityIncreasedcytokineandchemokinelevels;increasedlethality
Increasedcytokineandchemokinelevels;enhancedintestinaldamage;increasedmortality;celldeath
NoresponsetoDexintermsofleukocyteinfiltrationandcytokinesuppression
References(172)(173))(174)(175)(176)(177)(178)(179)(180)
InflammatoryDiseaseModelAnaphylaxis
Colitis
Diet-inducedobesity
Experimentalautoimmuneencephalomyelitis(EAE)
Experimentalinductionofarthritis(EIA)Experimentalperiodontitis
Hypoxia3pulmonaryhypertensionInfectionwithgram-negativebacteria3sepsisInfectionwithgram-positivebacteria
Influenzaviralinfection
Ischemia-reperfusioninjury
LPS-inducedendotoxemiaandsepticshockPolymicrobialperitonitis(CaspandCLP)Stress
TNF-inducedacuteinflammationZymosan-inducedinflammation
DefectiveCD4ϩ/CD8ϩTcellresponsesϾroleforJNK?
Inhibitionofp38
Inhibitionofp38andJNKNomechanismdescribedInhibitionofp38andJNKInhibitionofJNK-2Inhibitionofp38andJNK
(175)(181)(81,176,182–184)(185)(184,186)(59)(79)
CLP,cecalligationandpuncture;Dex,dexamethasone;eNOS,endothelialNOS;MOF,multipleorganfailure.
GC-inducedleucinezipper(GILZ)
Tsc22d3(encodingGC-inducedleucinezipperorGILZ)isconsideredaprototypeofaGC-inducedgeneandisthereforeoftenrepresentedasamerereadoutproductoftheGC-inducedsignalingcascade.However,italsome-diatestheeffectsofGCsinimmunefunction.GILZbe-longstothefamilyofTGF--stimulatedclone22domain(TSC22D)proteins.Thisfamilyincludesgenestranscrip-tionallyactivatedbyTGF-andGCsinawidevarietyofcelllinesandtissues(82–84).Tsc22d3inductionbyGCsisinhibitedinGRdim/dimmice(Ref.85;ourunpublishedresults).Moreover,theTsc22d3promoterregiondis-playssixputativeGREmotifs,aswellasmotifsforothertranscriptionfactors.TheGILZproteinhasbeenreportedtobindtoRasandRaf-1andthedownstreamproinflammatorytranscriptionfactorsNF-BandAP-1(86,87).Rasisamembrane-associatedproteinactivat-inganumberofsignalingcascades,includingtheRAF-MEK-ERKandphosphatidylinositol-3kinase-AKTpath-ways(88–90).Furthermore,bybindingtoRaf-1,GILZinhibitsMEKandERKphosphorylationandsubsequentactivation.Inthisway,GILZinductionseemstobeoneofthemechanismsbywhichGCsregulatetheMAPK-sig-nalingcascade,albeitindirectly.Next,GILZhasalsobeenshowntointeractwithp65(subunitofNF-B)andbothc-Fosandc-Jun(subunitsofAP-1)(86,91).Theseanti-inflammatorypropertiesofGILZindicateanimmunemodulatoryrole.Theanti-inflammatoryactionsofGILZhavebeenconfirmedbyusingmousemodelsofchronicinflammatorydiseases,suchasdinitrobenzenesulfonicacid(DNBS)-inducedcolitis(amodelofinflammatoryboweldisease)(92),collagen-inducedarthritis(CIA)(amurinemodelofRA)(93),andexperimentalautoimmuneencephalomyelitis(amodelofmultiplesclerosis[(MS])(94).TheuseofGILZ-overexpressingtransgenicmicedemonstratedthatGILZcanantagonizethedevelopment
Endocrinology,March2013,154(3):993–1007ofcolonicinflammationinducedbyDNBS(92).Inaddi-tion,invivodeliveryofTsc22d3smallinterferingRNAinCIAmiceincreaseddiseaseseverity,indicatingthatGILZhasanimportantprotectivefunction(93).Moreover,invitro,GILZsmallinterferingRNAinhibitedthesuppres-sionofLPS-inducedcytokinesbyGCs(95).Furthermore,GILZadministrationhadamoreprotectiveeffectthantheadministrationofhighdosesofGCsinbothDNBS-in-ducedcolitisandCIA.Inaddition,theanti-inflammatoryactionsofGCs(up-regulationofGILZuponGCtreat-menthasalsoproveneffective)inpatientssufferingfromalcoholichepatitis(AH)aredependentonGilz(96).Insummary,thesedatashowthatGILZisakeymediatoroftheanti-inflammatorypropertiesofGCs.
Annexin-1
Annexin-1orlipocortin-1(encodedbyAnxA1)isamemberoftheannexinsuperfamilyofcalcium-andphos-pholipid-bindingproteins(97).ThehumanAnxA1pro-moterregioncontainsaGREelement,butwhetheritcanbeinducedinGRdim/dimmicehasnotbeenreported(98).Annexin-1wasoriginallydescribedasaGC-inducedpro-teininhibitingtheactivityofphospholipaseA2,whichisknowntocleavearachidonyl-containingphosphatidesinthecell(99,100).Arachidonicacidcanbefurthermodi-fiedbycyclooxygenases(COX)toyieldtheproinflamma-torymediatorsprostaglandinsandleukotrienes.An-nexin-1alsoinhibitsNF-B,bybindingtothep65subunitandtherebypreventsitsbindingtoDNAandtoCOX-2(101–103).Neutralizingantibodiesagainstannexin-1ab-rogatedtheinhibitoryactionofGCsintherathindpawcarrageenanedemamodelandinaratischemia-reperfu-sioninjurymodel(104).StudiesonAnxA-1Ϫ/Ϫmiceshowedthatannexin-1isprotectiveinAIA,bleomycin-inducedlungfibrosis,anddextransodiumsulfate-in-ducedcolitis:thediseasesweremoresevereinAnxA-1Ϫ/Ϫmice(105–107).Ithasalsobeensuggestedthatannexin-1isprotectiveinCIA,ulcerativecolitis,andchronicgran-ulomatousinflammation(102,108,109).Moreover,GCsexertednoinhibitoryeffectsinAnxa-1Ϫ/Ϫmiceinacar-rageenan-orzymosan-inducedinflammatorymodelorinAIA,suggestingthatannexin-1mediatesanti-inflamma-toryactionsofGCs(107,110).Annexin-1wasalsoshowntomodulatetherepairofgastricmucosalinjury,becausetreatmentwithanannexin-1mimeticsignificantlyen-hancedgastriculcerhealing(111)andtheuseofanan-nexin-1-basedpeptide,MC-12,resultedinameliorationofsymptomsinbothdextransodiumsulfateand2,4,6-trinitrobenzenesulfonicacid-inducedcolitismodelsinmice(112).Insummary,thesefindingsraiseinterestinannexin-1asaGC-inducibleeffectorofinflammationresolution.
endo.endojournals.org1001
GR-mediatedTRofnGREgenes
Figure2explainshowGRdimersarealsorequiredforTRofnGREgenes(33,34).Theseso-callednGREele-ments,comparabletonormalGRE,arecomposedoftwoinvertedrepeats(hexanucleotides)thatareeitheradjacentorseparatedbyoneor2bp(CTCC(n)0–2GGAGA;re-ferredtoasIR0,IR1andIR2,respectively)(35).However,theanti-inflammatorycapacityofGR-mediatedTRofnGREgenesisunknown.Nevertheless,arecentstudybySurjitetal.(35)indicatedthatTRofnGREgenesbyGRdimerscantranscriptionallyrepresstheexpressionofthecytokinethymicstromallymphopoietinthroughdirectbindingofdimericGRtoanGRE.ThismechanismcouldaccountfortheGR-mediatedrestrictionofatopicderma-titis.ThesefindingssuggestthatthesensitivityofGRdim/dimmiceinseveraldiseasemodelscanalsobeaccountedforbyreducedTRofnGREgenes.ItwasreportedthatnGREsarepresentinmorethan1000mouse/humanorthologgenes,someofwhichareknowntoencodeproinflamma-torymediators,whichindicatestheimportanceofthismechanismasanadditionallevelofanti-inflammatoryGRsignaling(35).ThecontributionofnGREgenestotheanti-inflammatorycascadeofGRremainstobeeluci-dated,butneverthelessposesaninterestingfieldofinves-tigation.Thoroughinvestigation,forexamplebystudyingtheexpressionprofilesofthesegenesinGRdim/dimmice,couldleadtotheidentificationofnewanti-inflammatoryGRtargets.
GC-mediatedproinflammatoryeffects
Theabove-mentionedstudiesdemonstratethestronganti-inflammatoryactionsofGCs.However,GCsarenotexclusivelyimmunosuppressive(113);GCsalsoassistinmaintainingandevenfacilitatingimmunity.Forexample,adrenalectomizedmiceandpatientswithAddison’sdis-easeproducenoGCs,andbothofthesearemoresuscep-tibletoinfection(114).Indeed,ithasbeenreportedthatGCscanhaveenhancingeffectsonimmunecells(115).Forexample,ithasbeenreportedthatdependingonthecom-positionoftheGR-AP-1dimer,GRcaninfluencetheac-tivityAP-1eitherpositivelyornegatively(116).Also,dis-ruptionofGCactioninosteoblastsresultedinamorerapidresolutionofinflammationintheK/BxNmodelofexperimentalarthritis,suggestingthatGCshaveaproin-flammatoryroleinthismodel(117).Moreover,inaddi-tiontotheirimmunosuppressiveeffectonTLRsignaling,GCsalsoaffectTLRexpression.Forinstance,thepro-moterofTLR2iscooperativelystimulatedbyGCsandTNF,throughthepresenceofafunctionalNF-Bsite,aGREelement,andasignaltransducersandactivatorsoftranscription-bindingelement(118).Generally,GCsareimmunestimulatorywithinthenormalphysiologicrange
1002VandevyveretalAnti-inflammatoryPotentialofGRDimersofhypothalamic-pituitary-adrenalaxisactivityandinhib-itorywhenGClevelsarehigher,asinchronicallystressedanimals.ThesefindingsclearlyindicatetheeffectsofGCsarecriticallydosedependent:supraphysiologicdosesofGCsmostprobablyresultinthewidelyGC-mediatedanti-inflammatoryeffects,whereaslowerdosescanbeimmunomodulatory.
ConclusionandFuturePerspectives
InthisreviewweemphasizetheimportanceofGRdimerizationinthecombatagainst,orresolutionof,in-flammation.Itisgenerallybelievedthattheanti-inflam-matoryaspectofGRresultsfromTRofproinflammatorygenesbythetetheringofmonomericGRtoothertran-scriptionfactors.However,somerecentstudiesusingGRdim/dimmutantmiceindicatethatGRdimersalsoac-countfortheresolutionofinflammationbyGR.Thephys-iologyofGR,ie,itsisoforms,posttranslationalmodifica-tions,therecruitmentofcofactors,anditssubsequentactionsarestronglytissuespecific.Moreover,thereissub-stantialtemporalvariationinGC-mediatedactions,andthisisreflectedintime-dependentgene-specificinduction.ThismightexplainthediscordantreportsontheresponseofGRdim/dimmiceindistinctinflammatoryenvironments(Table1).Itisworthwhiletodecipherthetissue-andtime-specificeffectsofGCsbecauseitcouldresolvethecon-tradictionsinthereportedresultsandclarifytheroleofGRactionsinseveraldiseases.
Interestingly,thecontinuingidentificationofnewGRE-dependentgeneswithanti-inflammatorypropertiesdemonstratesthattheTApotentialofGRisindispensableandindicatesthatthemechanismoftheanti-inflamma-toryactionofGRisfarfromcompletelyunderstood,in-cludingtheunidentifiedroleofnGRE-dependentgenes.In-depthknowledgeofthesemechanismswillelucidatewhetherGRdimerizationpreventingGRligandsare,infact,potentialtherapeuticsinthecombatagainstinflam-mationormightbedangerousratherthanhelpfulinthisaspect.Indeed,manyscientistshavetriedtodevelopSEGRAsthatpreferentiallyinducetheformationofmonomers(33,35,42,119–121).However,onlytwocompoundshavemadeittoclinicaltrialsfortopicalap-plication.Thisisprobablyduetothefactthatanincreas-ingamountofdataisbeingpublishedontheimportanceofGRdimersintheresolutionofinflammation.Further-more,theabove-mentioneddogmaischallengedbydatashowingthatGRdim/dimmicestillsufferfromsomesideeffectsuponGCtreatment(122),whichmeansthatnotallsideeffectscanbeexplainedbyreducedGRTAactivity.AlthoughitwasdemonstratedthatGRdimersplayan
Endocrinology,March2013,154(3):993–1007
intricateroleinthedevelopmentofhyperglycemiaandwoundrepair(123,124),GCtherapyinGRdim/dimmicestillreducesboneformationandattenuatesosteoblastdif-ferentiation,bothofwhicharecharacteristicsofGC-in-ducedosteoporosis(85,123–125).Next,GRdim/dimmiceandGRwt/wtmiceshowthesamedegreeofmuscleatrophyuponGCtherapy,suggestingthatmonomericGRissuf-ficienttocauseskeletalmuscleatrophy(126).ThiscouldbebecausenotallgenesthatarepositivelyregulatedbyGRareaffectedbytheGRdim/dimmutation,suchasgenesde-pendentoncompositeelementsortetheringmechanisms(Figure2).Itmustbenotedthatitisdifficulttodifferen-tiatebetweenTAandTRbecausetheGRcoactivatorGR-interactingprotein1isalsorecruitedtositesofGRre-pression,indicatingthatitalsohasacorepressorfunction(20).ThesefindingsindicatethatGR-interactingprotein1hasadualfunction:facilitatingbothTAandTRaspectsofGRactiondependingonthegenomiccontext.Thisin-dicatesthatdissociatingcompoundswilllikelystillinducecertainunwantedsideeffects.Inaddition,SEGRAsmightnotactivateallthemechanismsofTRactions.Forexam-ple,compoundAeffectivelyblocksNF-B,butnotAP-1(Ref.127andourunpublisheddata).Moreover,anemergingroleforGR-dimer-mediatedTRofnGREgenesalsoquestionstheuseofSEGRAs.Sofar,themolecularmechanismsofGR-inducedrestrictionofinflammationarenotcompletelyunderstoodandposeaninterestingfieldofinvestigation.In-depthknowledgeofthesemech-anismswillelucidatewhetherGRligandsorSEGRAsarepotentialtherapeuticsforinflammation,orwhethertheycouldbedangerousbecausetheymightcauseimmunos-timulationincertaininflammatorydiseases.Here,wewanttostressthatthoroughstudiesareneededtounravelthemechanisticdetailsoftheanti-inflammatorycascadeofGR,inaninflammation-specificway.Hence,theiden-tificationandfurtheruseofSEGRAsobviouslyholdabraketothefullcascade.Theidentificationofdisease-specificGRagonistswillbenecessarytoreducepatientsufferinganddecreaseeconomiccosts.
Acknowledgments
Addressallcorrespondenceandrequestsforreprintsto:ClaudeLibert,VIB-DepartmentforMolecularBiomedicalResearch/Ugent,Technologiepark927,Zwijnaarde9052,Belgium.E-mail:Claude.libert@dmbr.vib-ugent.be.
DisclosureSummary:Theauthorshavenothingtodisclose.
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