Estrogen anti‐inflammatory activity on human monocytes is mediated through cross‐talk between estrogen receptor ERα36 and GPR30/GPER1

[摘要] Estrogensareknownmodulatorsofmonocyte/macrophagefunctions;however,theunderlyingmechanismhasnotbeenclearlydefined.Recently,anumberofestrogenreceptormoleculesandsplicevariantswereidentifiedthatexertdifferentandsometimesopposingactions.Weassessedtheexpressionofestrogenreceptorsandexploredtheirroleinmediatingestrogenicanti‐inflammatoryeffectsonhumanprimarymonocytes.Wereportthattheonlyestrogenreceptorsexpressedareestrogenreceptor‐α36‐kDasplicevariantandG‐proteincoupledreceptor30/G‐proteinestrogenreceptor1,inasex‐independentmanner.17‐β‐EstradiolinhibitstheLPS‐inducedIL‐6inflammatoryresponse,resultingininhibitionofNF‐κBtranscriptionalactivity.Thisisachievedviaadirectphysicalinteractionofligand‐activatedestrogenreceptor‐α36‐kDasplicevariantwiththep65componentofNF‐κBinthenucleus.G‐proteincoupledreceptor30/G‐proteinestrogenreceptor1,whichalsophysicallyinteractswithestrogenreceptor‐α36‐kDasplicevariant,actsacoregulatorinthisprocess,becauseitsinhibitionblockstheeffectofestrogensonIL‐6expression.However,itsactivationdoesnotmimictheeffectofestrogens,onneitherIL‐6norNF‐κBactivity.Finally,weshowthattheestrogenreceptorprofileobservedinmonocytesisnotmodifiedduringtheirdifferentiationtomacrophagesordendriticcellsinvitroandissharedinvivobymacrophagespresentinatheroscleroticplaques.Theseresultspositionestrogenreceptor‐α36‐kDasplicevariantandG‐proteincoupledreceptor30asimportantplayersandpotentialtherapeutictargetsinmonocyte/macrophage‐dependentinflammatoryprocesses...

[学科分类] 生理学

[关键词] macrophages;IL‐6;NF‐κB;atherosclerosis