Gastroenterology

Gastroenterology

Volume 140, Issue 1, January 2011, Pages 254-264.e2
Gastroenterology

Basic—Alimentary Tract
Colitis and Intestinal Inflammation in IL10−/− Mice Results From IL-13Rα2–Mediated Attenuation of IL-13 Activity

https://doi.org/10.1053/j.gastro.2010.09.047Get rights and content

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-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-13Rα2–mediated 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.

Section snippets

Animals

Female C57BL/6, BALB/c, BALB/c il13rα2−/−, il13rα1−/−, il10−/−, and il10−/−il13rα2−/− 6- to 8-week-old mice were obtained from Taconic (Hudson, NY). Animals were housed under specific pathogen-free conditions at the National Institutes of Health in an American Association for the Accreditation of Laboratory Animal Care–approved facility. The National Institute of Allergy and Infectious Diseases Animal Care and Use Committee approved all experimental procedures. A minimum of 5 mice per group was

IL-17A and IFN-γ–Associated Colitis Is Reduced in the Absence of IL-13Rα2

IL-10 is a critical immunoregulatory cytokine that maintains intestinal homeostasis and symbiosis with enteric microflora. Germline deletion of IL-10 in mice results in spontaneous colitis after 3 to 4 months, driven by dysregulated immune responses to colonic flora.16 The onset of colitis can be accelerated and synchronized by feeding mice piroxicam, a nonsteroidal anti-inflammatory drug.23 It has been shown that piroxicam-induced colitis in il10−/− mice is attenuated following intestinal

Discussion

Following piroxicam treatment or infection with T muris, IFN-γ– and IL-17A–driven intestinal inflammation correlated with elevated IL-13Rα2 levels. Deletion of IL-13Rα2 abrogated IFN-γ and IL-17A and significantly attenuated the degree of inflammation in both models. These data suggest that IL-13Rα2 is directly responsible for the development of inflammation, as suggested in a different model of colitis.25 Alternatively, these observations suggest that IL-13Rα2 was blocking IL-1322, 24 and that

Acknowledgments

Dr Wilson's current affiliation is: National Institutes for Medical Research, Medical Research Council, London, England.

The authors thank Nicole Mahoney, Joy McFarlane, Jose Encarnacion, Lauren Donato, and SoBran staff for meticulous care of all animals; Mary Collins and Marion Kasaian at Wyeth LLC for providing IL-13Rα2–deficient mice; Sandra D. White, Robert W. Thompson, and National Institutes of Health Clinical Center staff for additional animal care, technical assistance, and complete

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. David Artis is funded by National Institutes of Health grant nos. AI61570 and Crohn's and Colitis Foundation of America's William and Shelby Modell Family Foundation Research Award.

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