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IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6
David Yen, … , Robert A. Kastelein, Donna Rennick
David Yen, … , Robert A. Kastelein, Donna Rennick
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1310-1316. https://doi.org/10.1172/JCI21404.
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Research Article Immunology

IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6

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Abstract

Uncontrolled mucosal immunity in the gastrointestinal tract of humans results in chronic inflammatory bowel disease (IBD), such as Crohn disease and ulcerative colitis. In early clinical trials as well as in animal models, IL-12 has been implicated as a major mediator of these diseases based on the ability of anti-p40 mAb treatment to reverse intestinal inflammation. The cytokine IL-23 shares the same p40 subunit with IL-12, and the anti-p40 mAbs used in human and mouse IBD studies neutralized the activities of both IL-12 and IL-23. IL-10–deficient mice spontaneously develop enterocolitis. To determine how IL-23 contributes to intestinal inflammation, we studied the disease susceptibility in the absence of either IL-23 or IL-12 in this model, as well as the ability of recombinant IL-23 to exacerbate IBD induced by T cell transfer. Our study shows that in these models, IL-23 is essential for manifestation of chronic intestinal inflammation, whereas IL-12 is not. A critical target of IL-23 is a unique subset of tissue-homing memory T cells, which are specifically activated by IL-23 to produce the proinflammatory mediators IL-17 and IL-6. This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases.

Authors

David Yen, Jeanne Cheung, Heleen Scheerens, Frédérique Poulet, Terrill McClanahan, Brent Mckenzie, Melanie A. Kleinschek, Alex Owyang, Jeanine Mattson, Wendy Blumenschein, Erin Murphy, Manjiri Sathe, Daniel J. Cua, Robert A. Kastelein, Donna Rennick

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Figure 5

IL-23, but not IL-12, specifically stimulates a subset of memory CD4+ T cells that produce IL-17.

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                  IL-23, but not IL-12, specifically stimulates a subse...
FACS-purified CD4+CD45RBlow splenic T cells (2 × 105/ml; >95% purity) were isolated and cultured on CD3-coated plates. (A) Cytokine production by memory CD4+ T cells. Supernatants from cells stimulated with IL-23 (10 ng/ml) or IL-12 (1 ng/ml) were analyzed by ELISA. (B) IL-23–dependent proliferation of memory CD4+ T cells was assessed by[3H]-thymidine incorporation after 4 days of culture on anti-CD3 mAb–coated plates in the presence of anti–IL-2 mAb. (C) FACS analysis of memory CD4+ T cells from IL-10 –KO and IL-10 × p19–KO mice after cells were stained for intracellular IL-4, IL-17, and IFN-γ proteins.

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