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Anti-inflammatoryeffectsofshortchainfattyacidsinIFN-γ-stimulatedRAW264.7murinemacrophagecells:InvolvementofNF-κBandERKsignalingpathwaysJin-SunPark,Eun-JungLee,Jae-ChulLee,Won-KiKim,Hee-SunKim⁎DepartmentofNeuroscienceandMedicalResearchInstitute,CollegeofMedicine,EwhaWomansUniversity,Mok-6-dong911-1,Yangchun-Ku,Seoul158-710,SouthKoreaReceived18July2006;receivedinrevisedform26August2006;accepted29August2006AbstractTheoveractivationofmacrophagescausesabnormalcelldeathandchronicinflammatorydiseases.Therefore,themodulationofmacrophage-mediatedcytotoxicityisexpectedtobecomeanewtherapeuticstrategyforvariousinflammatorydiseases.Inthisstudy,threetypesofshortchainfattyacids(sodiumbutyrate(NaB),sodiumphenylbutyrate(NaPB),sodiumphenylacetate(NaPA))werefoundtohaveanti-inflammatoryeffectsinIFN-γ-stimulatedRAW264.7cells.TheyinhibitedtheexpressionofiNOS,TNF-α,andIL-6inducedbyIFN-γ,whiletheyenhancedtheexpressionoftheanti-inflammatorycytokine,IL-10.Theirpotencyasanti-inflammatoryagentswasintheorderofNaBNNaPBNNaPA.FurthermechanisticstudiesrevealedthesethreeagentstorepresstheDNAbindingandtranscriptionalactivitiesofNF-κB,whichisanimportantmodulatorofinflammation.Inaddition,theseagentsrepressedtheIFN-γ-inducedERK1/2phosphorylationwithoutaffectingtheJak/STATactivities.ThepotencyofNF-κBandERKinhibitionwasalsointheorderofNaBNNaPBNNaPA.TheresultssuggestthattheNF-κBandERKsignalingpathwaysareatleastinpartinvolvedintheanti-inflammatoryactivitiesoftheseSCFAs.ConsideringthatSCFAsarenormallypresentinthebodyandhavefewsideeffects,theymightbepromisingagentsforthepreventionand/ortreatmentofvariousinflammatorydiseases.©2006ElsevierB.V.Allrightsreserved.Keywords:Shortchainfattyacids;Macrophage;Cytokine;iNOS;NF-κB;ERK1.IntroductionMacrophagesplayimportantrolesinvariousinflam-matoryresponses,immunity,hostdefense,andtissuerepair.Onceactivated,macrophagessecretealargenumberofpro-inflammatorycytokines,chemokines,nitricoxideandproteasesandinducetheapoptosisofresidentstromalandparenchymalcells[1].Macro-phagesremoveapoptoticcellsbyphagocytosisandsecreteanti-inflammatorymediatorsandgrowthfactors,whichleadstowoundhealingandrepair[1,2].There-fore,macrophagecellshaveambiguousfunctions,suchInternationalImmunopharmacology7(2007)70–77www.elsevier.com/locate/intimpAbbreviations:SCFA,shortchainfattyacid;NaB,sodiumbutyrate;NaPB,sodiumphenylbutyrate;NaPA,sodiumphenylacetate;NO,nitricoxide;iNOS,induciblenitricoxidesynthase;IFN,interferon;GAS,gamma-activatedsequence;Jak,Janustyrosinekinase;STAT,signaltransducerandactivatoroftranscription;ERK,extracellularsignal-regulatedkinase;NF-κB,nuclearfactor-kappaB.⁎Correspondingauthor.Tel.:+82226505823;fax:+82226538891.E-mailaddress:hskimp@ewha.ac.kr(H.-S.Kim).1567-5769/$-seefrontmatter©2006ElsevierB.V.Allrightsreserved.doi:10.1016/j.intimp.2006.08.015asinducingoralleviatinginflammationdependingontheiractivationstatus.Acorrectbalancebetweenthesetwopopulationsisneededforhealingandresolution.However,anexcessnumberofactivatedmacrophagescaninduceabnormalcelldeathandchronicinflammatorydiseasessuchasrheumatoidarthritis,glomerulonephritis,atherosclerosisandvariousneurodegenerativediseasesincludingAlzheimer'sdiseases[3–6].Therefore,themodulationofthemacrophage-mediatedinflammatoryresponsesisemergingasapromisingnewtherapeuticapproachagainsttheseinflammatorydiseases.Shortchainfattya...