IL-23 cross-regulates IL-12 production in T cell dependent experimental colitis

IL-12 is a key regulatory cytokine in cell-mediated immunity and induces the differentiation of naïve T cells towards a TH1 phenotype. The pathogenic activity of IL-12 has been demonstrated in various TH1-mediated experimental models of autoimmune diseases including inflammatory bowel disease (IBD). Moreover, a recent clinical trial showed that targeting of the p40 subunit of IL-12 by neutralizing antibodies suppresses gut inflammation in patients with Crohn's disease. However, since the recently discovered IL-23 shares the p40 subunit with IL-12, the role of IL-12 may have been overestimated in studies using neutralizing p40 antibodies. The discovery that IL-23 but not IL-12 is essential in some models of chronic inflammation and autoimmunity led to a model in which IL-12 is required to induce IFN-gamma producing TH1 cells while IL-23 mediates TH1 effector functions.

To investigate the role of IL-23 in chronic intestinal inflammation, we created a novel knockout mouse in which the endogenous IL-23 p19 gene was replaced by the LacZ expression cassette. We describe here that such newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19 deficient mice produce elevated levels of IL-12 and that IL-23 downregulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23 deficient mice rescued mice from lethal colitis. Together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis. Our data implicate that treatment of such colitis may require inactivation of both IL-12 and IL-23.