Abstract
Abstract IBD is a chronic intestinal inflammatory disease that often has extra-intestinal manifestations. We examined the role of the MAPK phosphatase Mkp-1 in a mouse model of IBD. Mkp-1+/+/Il-10+/+, Mkp-1-/-/Il-10+/+, Mkp-1+/+/Il-10-/-, and Mkp-1-/-/Il-10-/- (dKO) mice on a 129 background were housed in a specific pathogen-free environment. Colitis signs were evaluated using a clinical scoring system, histological examination, and cytokine analysis. Most dKO mice developed severe rectal prolapse, peri-ocular lesions, and high clinical scores, signs generally not seen in Il-10 KO mice. dKO colons had extensive chronic and neutrophilic colitis, mucosal hyperplasia, and higher histological IBD scores than Il-10 KO colons. dKO eyelids and conjunctival mucosa were thickened and had neutrophilic and lymphoplasmocytic conjunctivitis. After LPS treatment, splenocytes and lymph node cells isolated from dKO mice had more robust production of Th-1 cytokines than cells from Il-10 KO mice. dKO colons contained higher levels of Th-1 cytokines and IL-17, and exhibited greater p38 and ERK activation, than did Il-10 KO colons. These data indicate that loss of Mkp-1 skews host immunity towards an exaggerated Th-1/Th-17 response and provide novel insights on the interaction between Mkp-1 and IL-10 in colitis models. Our studies support a pivotal role of Mkp-1 as a brake in the mucosal immune response to limit IBD development.
Published Version
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