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

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 6

Blocking IL-6 and IL-17 significantly reduced the intestinal inflammation, by 50%.

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Blocking IL-6 and IL-17 significantly reduced the intestinal inflammatio...
Recipient mice were dosed i.p. with isotype, anti–IL-6, anti–IL-17, or anti–IL-6 plus anti–IL-17 Abs (2 mg/mouse) a day prior to T cell reconstitution. Rag-KO mice were reconstituted with sorted splenic CD4+CD45RBhi (naive) T cells (5 × 105 cells/mouse) from diseased IL-10 –KO mice and treated daily with 1 μg/mouse IL-23 protein. Subsequent rounds of Ab were administered weekly for 6 weeks. The graph shows the path scores from 2 independent but identical experiments. The disease scores for each group were obtained as previously described (41). Horizontal bars represent the median value for each group. **P < 0.05, compared with isotype Ab (unpaired Student’s t test). Histologic examination was performed and scored using formalin-fixed tissue sections stained with H&E, as previously described (40).