Colitis and intestinal inflammation in IL10-/- mice results from IL-13Rα2-mediated attenuation of IL-13 activity.
OBJECTIVE
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.
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Mark S
MS
Wilson
Thirumalai R
TR
Ramalingam
Aymeric
A
Rivollier
Kevin
K
Shenderov
Margaret M
MM
Mentink-Kane
Satish K
SK
Madala
Allen W
AW
Cheever
David
D
Artis
Brian L
BL
Kelsall
Thomas A
TA
Wynn
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D005260:Female; D005759:Gastroenteritis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010894:Piroxicam / Q000633:toxicity; D014257:Trichuriasis / Q000276:immunology / Q000382:microbiology
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D020381:Interleukin-17; D016753:Interleukin-10; D010894:Piroxicam; D007371:Interferon-gamma