title: Knockout of Mkp-1 exacerbates colitis in Il-10-deficient mice.
abstract: Il-10-deficient mice develop colitis associated with exaggerated Th1/Th17 responses and are a valuable model of inflammatory bowel disease. Mkp-1 is a major negative regulator of MAPKs, and its expression is enhanced by IL-10. To understand the role of Mkp-1 in the regulation of intestinal mucosal immune responses, we studied the effect of Mkp-1 deletion on the pathogenesis of colitis in Il-10(-/-) mice. We found that knockout of Mkp-1 on an Il-10(-/-) background accelerated the development of colitis. Compared with Il-10(-/-) mice, colitis not only appeared earlier but also was more severe in Il-10(-/-)/Mkp-1(-/-) mice. Il-10(-/-) mice exhibited a mild intestinal inflammation in the specific pathogen-free environment, and rectal prolapse rarely appeared before 6 mo of age. In contrast, the majority of Il-10(-/-)/Mkp-1(-/-) mice developed severe colitis rapidly and presented with rectal prolapse after only 2-3 mo. The colon of Il-10(-/-)/Mkp-1(-/-) mice showed diffuse transmural chronic inflammation and mucosal hyperplasia, with significantly more proliferating crypt epithelial cells than those of Il-10(-/-) mice. In addition to the severe colitis, Il-10(-/-)/Mkp-1(-/-) mice also developed conjunctivitis and blepharitis. The colon of Il-10(-/-)/Mkp-1(-/-) mice contained significantly higher levels of proinflammatory cytokines and exhibited greater MAPK activities than did the colon of Il-10(-/-) mice. Splenocytes and lymphocytes from Il-10(-/-)/Mkp-1(-/-) mice produced higher levels of Th1 cytokines ex vivo upon activation than did cells from Il-10(-/-) mice. Our studies support a pivotal role of Mkp-1 as a negative regulator of mucosal immune responses and highlight its protective function against inflammatory bowel disease.
authors.affiliation: Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, USA.
authors.forename: Ranyia
authors.initials: R
authors.lastname: Matta
authors.forename: John A
authors.initials: JA
authors.lastname: Barnard
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Wancket
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.forename: Jianjing
authors.initials: J
authors.lastname: Xue
authors.forename: Jessica
authors.initials: J
authors.lastname: Grieves
authors.forename: W Joshua
authors.initials: WJ
authors.lastname: Frazier
authors.forename: Leif
authors.initials: L
authors.lastname: Nelin
authors.forename: Andrew C B
authors.initials: AC
authors.lastname: Cato
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001762:Blepharitis / Q000235:genetics / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003231:Conjunctivitis / Q000235:genetics / Q000473:pathology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016753:Interleukin-10; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse