Redox regulation of MMP-3/TIMP-1 ratio in intestinal myofibroblasts: Effect of N-acetylcysteine and curcumin

Matrix metalloproteinases(MMPs)playacriticalroleininflammation andulcerationsingutof Crohn's disease(CD)patients.Intestinalsubepithelialmyofibroblasts (ISEMFs)secreteMMPsin response toinflammatory stimuli.PreviousdatashowedinCD-ISEMFsincreasedoxidativestatus. The aimofthisstudywastoinvestigatetheroleofISEMFsinmodulatingtheproductionofMMP- 3 andTIMP-1,aninhibitorofMMPsactivity.Arelationshipamongoxidativestress,activityof antioxidantsandMMP-3/TIMP-1wasalsostudied.ISEMFsisolatedfromCDpatientcolonand human coloniccelllineofmyofibroblasts (18Co)wereused.Oxidativestatewasmodulatedby buthionine sulfoximine,aninhibitorofglutathione(GSH)synthesis,andN-acetylcysteine(NAC), GSH precursor.Anup-regulationofMMP-3duetoincreasedoxidativestatewasfoundinCD- ISEMFs. Stimulationbytumornecrosisfactor(TNF)α increased furtherMMP-3levels.Onthe contrary,nochangeinTIMP-1productionwasdetermined.NACtreatmentdecreasedMMP-3 production inCD-ISMEFsandremovedtheenhancementduetoTNFα. Similareffectswere observed in18Cocellstreatedwithcurcumin,antioxidantwithanti-inflammatory properties.The involvementofMAPKsonMMP-3redoxregulationwasalsoshown.Thisstudydemonstratesthe involvementofISEMFsandhighoxidativestateintheincreasedMMP-3productionfoundin intestinal mucosaofCDpatients.NACandcurcuminnormalizeMMP-3levelsmainlyinTNFα stimulated cells.AmodulationofMMP-3productionbyNACandcurcuminduetotheirdirect action ontranscriptionalfactorshasbeenalsosuggested.Therefore,theycouldhaveatherapeutic use forthepreventionandtreatmentof fistulaes inCD