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-13Rα2). Methods: We examined the roles of IL-13 and IL-13Rα2 in intestinal inflammation in mice. To study the function of IL-13Rα2, il10-/- mice were crossed with il13rα2-/- to generate il10-/- il13rα2-/- double knockout (dKO) mice. Colitis was induced with the gastrointestinal toxin piroxicam or Trichuris muris infection. Results: Induction of colitis by interferon (IFN)-γ or IL-17 in IL-10 null mice requires IL-13Rα2. Following exposure of il10-/- mice to piroxicam or infection with T muris, production of IL-13Rα2 increased, resulting in decreased IL-13 bioactivity and increased inflammation in response to IFN-γ 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-γ and IL-17mediated 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-13Rα2mediated attenuation of IL-13 activity. In the absence of IL-13Rα2, IL-13 suppresses proinflammatory Th1 and Th17 responses. Reagents that block the IL-13 decoy receptor IL-13Rα2 might be developed for inflammatory bowel disease associated with increased levels of IFN-γ and IL-17.
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