SIK inhibition in human myeloid cells modulates TLR and IL‐1R signaling and induces an anti‐inflammatory phenotype

[摘要] Macrophagepolarizationintoaphenotypeproducinghighlevelsofanti‐inflammatoryIL‐10andlowlevelsofproinflammatoryIL‐12andTNF‐αcytokinesplaysapivotalroleintheresolutionofinflammation.Salt‐induciblekinasessynergizewithTLRsignalingtorestricttheformationofthesemacrophages.Theexpressionandfunctionofsalt‐induciblekinaseinprimaryhumanmyeloidcellsarepoorlycharacterized.Here,wedemonstratedthatthedifferentiationfromperipheralbloodmonocytestomacrophagesordendriticcellsinducedamarkedup‐regulationofsalt‐induciblekinaseproteinexpression.Withtheuseof2structurallyunrelated,selectivesalt‐induciblekinaseinhibitors,HG‐9‐91‐01andARN‐3236,weshowedthatsalt‐induciblekinaseinhibitionsignificantlydecreasedproinflammatorycytokines(TNF‐α,IL‐6,IL‐1β,andIL‐12p40)andincreasedIL‐10secretionbyhumanmyeloidcellsstimulatedwithTLR2and‐4agonists.Differentlythaninmousecells,salt‐induciblekinaseinhibitiondidnotenhanceIL‐1Raproductioninhumanmacrophages.Salt‐induciblekinaseinhibitionblockedseveralmarkersofproinflammatory(LPS+IFN‐γ)‐polarizedmacrophages[M(LPS+IFN‐γ)]andinducedaphenotypecharacterizedbylowTNF‐α/IL‐6/IL‐12p70andhighIL‐10.Thedownstreameffectsobservedwithsalt‐induciblekinaseinhibitorsoncytokinemodulationcorrelatedwithdirectsalt‐induciblekinasetarget(CREB‐regulatedtranscriptioncoactivator3andhistonedeacetylase4)dephosphorylationinthesecells.Moreimportantly,weshowedforthefirsttimethatsalt‐induciblekinaseinhibitiondecreasesproinflammatorycytokinesinhumanmyeloidcellsuponIL‐1Rstimulation.Altogether,ourresultsexpandthepotentialtherapeuticuseofsalt‐induciblekinaseinhibitorsinimmune‐mediatedinflammatorydiseases...

[学科分类] 生理学

[关键词] macrophages;monocytes;dendritic cells;inflammation