Differential role of IL-23 and IL-17 in intestinal regulation. Mus musculus

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of these cytokines is effective for treating psoriasis, IL-12/23 inhibition attenuates Crohn's disease, while IL-17A or IL-17RA inhibition exacerbates disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the mdr1a- /- mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing Treg accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provides insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited. Overall design: Mdr1a-deficient mice were infected with Helicobacter bilis to induce colitis and the role of different cytokines in disease compared by treatment with blocking antibodies. To that end, H. bilis-infected mice were treated with IL-23-, IL-23-/12- and IL-17RA-blocking antibodies and isotype control antibody and PBS control as well as an uninfected group in experiment 1. In a second experiment, H. bilis-infected mice were treated with IL-17A- and IL-17RA-blocking antibodies, isotype control antibody and PBS control as well as an uninfected group. Total RNA was extracted from the colon of each mouse and Affymetrix microarray profiles of each cytokine-blocking antibody group compared to control groups to understand the different effects of inhibiting IL-17A, IL-23, IL-23/12 and IL-17RA in this model of colitis. There were 3 to 5 mice in each antibody treatment group for a total of 42 samples across the 2 studies.