title: Butyrate attenuates lipopolysaccharide-induced inflammation in intestinal cells and Crohn's mucosa through modulation of antioxidant defense machinery.
abstract: Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CrD). High levels of Reactive Oxygen Species (ROS) induce the activation of the redox-sensitive nuclear transcription factor kappa-B (NF-κB), which in turn triggers the inflammatory mediators. Butyrate decreases pro-inflammatory cytokine expression by the lamina propria mononuclear cells in CrD patients via inhibition of NF-κB activation, but how it reduces inflammation is still unclear. We suggest that butyrate controls ROS mediated NF-κB activation and thus mucosal inflammation in intestinal epithelial cells and in CrD colonic mucosa by triggering intracellular antioxidant defense systems. Intestinal epithelial Caco-2 cells and colonic mucosa from 14 patients with CrD and 12 controls were challenged with or without lipopolysaccaride from Escherichia coli (EC-LPS) in presence or absence of butyrate for 4 and 24 h. The effects of butyrate on oxidative stress, p42/44 MAP kinase phosphorylation, p65-NF-κB activation and mucosal inflammation were investigated by real time PCR, western blot and confocal microscopy. Our results suggest that EC-LPS challenge induces a decrease in Gluthation-S-Transferase-alpha (GSTA1/A2) mRNA levels, protein expression and catalytic activity; enhanced levels of ROS induced by EC-LPS challenge mediates p65-NF-κB activation and inflammatory response in Caco-2 cells and in CrD colonic mucosa. Furthermore butyrate treatment was seen to restore GSTA1/A2 mRNA levels, protein expression and catalytic activity and to control NF-κB activation, COX-2, ICAM-1 and the release of pro-inflammatory cytokine. In conclusion, butyrate rescues the redox machinery and controls the intracellular ROS balance thus switching off EC-LPS induced inflammatory response in intestinal epithelial cells and in CrD colonic mucosa.
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University of Naples, Napoli, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Luciani
authors.forename: Paola
authors.initials: P
authors.lastname: De Cicco
authors.forename: Edoardo
authors.initials: E
authors.lastname: Troncone
authors.forename: Carolina
authors.initials: C
authors.lastname: Ciacci
mesh_terms: D000293:Adolescent; D000328:Adult; D000975:Antioxidants / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
chemical_list: D000975:Antioxidants; D002087:Butyrates; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha