Colitis and intestinal inflammation in IL10-/- mice results from IL-13R?2-mediated attenuation of IL-13 activity.

ABSTRACT: BACKGROUND & AIMS:The cytokine interleukin (IL)-10 is required to maintain immune homeostasis in the gastrointestinal tract. IL-10 null mice spontaneously develop colitis or are more susceptible to induction of colitis by infections, drugs, and autoimmune reactions. IL-13 regulates inflammatory conditions; its activity might be compromised by the IL-13 decoy receptor (IL-13R?2). METHODS:We examined the roles of IL-13 and IL-13R?2 in intestinal inflammation in mice. To study the function of IL-13R?2, il10(-/-) mice were crossed with il13r?2(-/-) to generate il10(-/-)il13r?2(-/-) double knockout (dKO) mice. Colitis was induced with the gastrointestinal toxin piroxicam or Trichuris muris infection. RESULTS:Induction of colitis by interferon (IFN)-? or IL-17 in IL-10 null mice requires IL-13R?2. Following exposure of il10(-/-) mice to piroxicam or infection with T muris, production of IL-13R?2 increased, resulting in decreased IL-13 bioactivity and increased inflammation in response to IFN-? or IL-17A. In contrast to il10(-/-) mice, dKO mice were resistant to piroxicam-induced colitis; they also developed less severe colitis during chronic infection with T muris infection. In both models, resistance to IFN-? and IL-17-mediated intestinal inflammation was associated with increased IL-13 activity. Susceptibility to colitis was restored when the dKO mice were injected with monoclonal antibodies against IL-13, confirming its protective role. CONCLUSIONS:Colitis and intestinal inflammation in IL10(-/-) mice results from IL-13R?2-mediated attenuation of IL-13 activity. In the absence of IL-13R?2, IL-13 suppresses proinflammatory Th1 and Th17 responses. Reagents that block the IL-13 decoy receptor IL-13R?2 might be developed for inflammatory bowel disease associated with increased levels of IFN-? and IL-17.

SUBMITTER: Wilson MS 

PROVIDER: S-EPMC3006653 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature