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

TLDR

Uncontrolled mucosal immunity in the gut drives chronic inflammatory bowel disease, and while IL‑12 has been implicated, IL‑23—sharing the p40 subunit—has also been targeted by anti‑p40 antibodies, and IL‑10‑deficient mice spontaneously develop enterocolitis. The study aimed to determine how IL‑23 contributes to intestinal inflammation. Researchers examined disease susceptibility in mice lacking IL‑23 or IL‑12 and assessed whether recombinant IL‑23 could worsen T‑cell transfer–induced colitis. They found that IL‑23 is essential for chronic intestinal inflammation, whereas IL‑12 is not; IL‑23 activates a unique subset of tissue‑homing memory T cells that produce IL‑17 and IL‑6, a pathway that may underlie chronic intestinal and other autoimmune inflammatory diseases.

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.