title: Catestatin decreases macrophage function in two mouse models of experimental colitis.
abstract: Mucosal inflammation in patients with inflammatory bowel disease (IBD) is characterized by an alteration of prohormone chromogranin A (CgA) production. The recent demonstration of an implication of CgA in collagenous colitis and immune regulation provides a potential link between CgA-derived peptides (catestatin, CTS) and gut inflammation. Colitis was induced by administration of dextran sulfate sodium or 2, 4 dinitrobenzenesulfonic acid to C57BL/6 mice. Treatment with human (h)CTS or its proximal or distal part was started one day before colitis induction and colonic inflammatory markers were determined. Pro-inflammatory cytokines were evaluated in peritoneal isolated and bone marrow derived macrophages (BMDMs); p-STAT3 level was studied. Serum levels of CgA and CTS were assessed in experimental colitis and in a separate study in IBD patients and healthy controls. We show that sera from IBD patients and that in experimental colitis conditions the colonic level of mouse (m)CgA and mCTS are significantly increased. Moreover, in vivo treatment with human (h)CTS reduces the disease onset and suppresses exacerbated inflammatory responses in preclinical settings of colitis associated with an increase of p-STAT3. In vitro, hCTS treatment decreases proinflammatory cytokine release by peritoneal macrophages and BMDMs and increases p-STAT3 levels. These results support the hypothesis that CTS is increased during colitis and that hCTS modulates intestinal inflammation via the macrophage population and through a STAT-3 dependent pathway in a murine model of colitis. Identification of the molecular mechanism underlying the protective role of this peptide may lead to a novel therapeutic option in IBD.
authors.affiliation: University of Manitoba, Department of Immunology, Winnipeg, MB, Canada.
authors.forename: Mohammad F
authors.initials: MF
authors.lastname: Rabbi
authors.affiliation: University of Manitoba, Department of Immunology, Winnipeg, MB, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Labis
authors.affiliation: Université de Strasbourg, Biomatériaux et Ingénierie tissulaire, INSERM U1121, 1 Place de l'Hôpital, 67091 Strasbourg, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Metz-Boutigue
authors.affiliation: University of Manitoba, IBD Clinical and Research Centre and Section of Gastroenterology, Winnipeg, MB, Canada.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Bernstein
authors.affiliation: University of Manitoba, Department of Immunology, Winnipeg, MB, Canada; University of Manitoba, IBD Clinical and Research Centre and Section of Gastroenterology, Winnipeg, MB, Canada. Electronic address: jeghia@yahoo.fr.
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Ghia
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000633:toxicity; D053379:Chromogranin A / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy*; D016264:Dextran Sulfate / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D044967:Serum
chemical_list: D001557:Benzenesulfonates; D053379:Chromogranin A; D010446:Peptide Fragments; D050796:STAT3 Transcription Factor; C109084:chromogranin A (344-364); C001073:2,4-dinitrobenzenesulfonic acid; D016264:Dextran Sulfate
keywords: Catestatin; Chromogranin A; Experimental colitis; Macrophages; STAT3