Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll‐like receptor 4 agonist LPS

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: HDAC6;    histone deacetylase;    inflammation;    sepsis;    SAHA;    TLR;   

DOI  :  10.1189/jlb.0509363

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Broad‐spectruminhibitorsofHDACsaretherapeuticinmanyinflammatorydiseasemodelsbutexacerbateddiseaseinamousemodelofatherosclerosis.HDACinhibitorshaveanti‐andproinflammatoryeffectsonmacrophagesinvitro.Wereportherethatseveralbroad‐spectrumHDACinhibitors,includingTSAandSAHA,suppressedtheLPS‐inducedmRNAexpressionoftheproinflammatorymediatorsEdn‐1,Ccl‐7/MCP‐3,andIl‐12p40butamplifiedtheexpressionoftheproatherogenicfactorsCox‐2andPai‐1/serpine1inprimarymouseBMM.SimilareffectswerealsoapparentinLPS‐stimulatedTEPMandHMDM.Thepro‐andanti‐inflammatoryeffectsofTSAwereseparableoveraconcentrationrange,implyingthatindividualHDACshavedifferentialeffectsonmacrophageinflammatoryresponses.TheHDAC1‐selectiveinhibitor,MS‐275,retainedproinflammatoryeffects(amplificationofLPS‐inducedexpressionofCox‐2andPai‐1inBMM)butsuppressedonlysomeinflammatoryresponses.Incontrast,17a(areportedlyHDAC6‐selectiveinhibitor)retainedanti‐inflammatorybutnotproinflammatoryproperties.Despitethis,HDAC6−/−macrophagesshowednormalLPS‐inducedexpressionofHDAC‐dependentinflammatorygenes,arguingthattheanti‐inflammatoryeffectsof17aarenotaresultofinhibitionofHDAC6alone.Thus,17aprovidesatooltoidentifyindividualHDACswithproinflammatoryproperties...

【 授权许可】

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