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Knockout of Mkp-1 exacerbates colitis in Il-10-deficient mice.

Authors: Matta, R  Barnard, JA  Wancket, LM  Yan, J  Xue, J  Grieves, J  Frazier, WJ  Nelin, L  Cato, AC  Liu, Y 
Citation: Matta R, etal., Am J Physiol Gastrointest Liver Physiol. 2012 Jun 1;302(11):G1322-35. doi: 10.1152/ajpgi.00018.2012. Epub 2012 Mar 29.
Pubmed: (View Article at PubMed) PMID:22461024
DOI: Full-text: DOI:10.1152/ajpgi.00018.2012

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.


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CRRD Object Information
CRRD ID: 7771532
Created: 2013-12-18
Species: All species
Last Modified: 2013-12-18
Status: ACTIVE


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