2473) and Kullberg et al. (page 2485) reveals that the cytokine IL-12 was merely a cover for the real IBD culprit, IL-23. IL-23 promotes inflammation by corrupting not only adaptive immunity, as previously thought, but also the innate immune system.
IL-12, an activator of adaptive immunity via the induction of Th1 cells, is composed of two subunits, p35 and p40. In mouse models of intestinal inflammation, antibodies against p40 prevent the chronic inflammation that occurs in IBD in response to intestinal bacteria. Thus, IL-12 was considered responsible for driving IBD.
Case closed? Not quite. In 2000, it was discovered that p40 can also dimerize with p19 to form IL-23. Thus, all studies using antibodies against p40, including studies of other autoimmune diseases (see J. Exp. Med. 201:163), required reevaluation. Using mouse models of IBD, Kullberg et al. show that mice incapable of producing p35 but still able to produce the p40 subunit develop intestinal inflammation in response to bacterial challenge, whereas mice that lack IL-23 resist the disease. Furthermore, Hue et al. show that an anti-p19 antibody strongly inhibits bacterially induced intestinal inflammation.
IL-23, which shows increased expression in mice with intestinal inflammation, was previously thought to activate adaptive Th17 cells only. But here, Kullberg et al. show evidence that both Th1 and Th17 cells may be overactivated by IL-23. Hue et al. also show, using mice that lack B and T lymphocytes, that IL-23 can also induce intestinal inflammation via the innate immune system. It remains to be determined both how IL-23 controls these diverse responses and what leads to its own overexpression in IBD.