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

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. [ABSTRACT FROM AUTHOR]