IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice

T-helper-1 (Th1) cytokines play an important role in Crohn's disease, and interleukin-12 (IL-12), which is composed of two subunits, p40 and p35, drives Th1 differentiation. In previous reports, IL-12 p40 was shown to prevent IL-12 from binding to the receptor. We demonstrate here the effect of IL-12 p40 overexpression in intestinal epithelia on enterocolitis mediated by Th1 cells in IL-10-deficient (IL-10(-/-)) mice on a C57BL/6J background. IL-10 deficient (IL-10(-/-))/ T3(b)-IL-12 p40(+)(IL-12 p40(+)) mice and IL- 10(-/-)/ T3(b)-IL-12 p40(-) (IL-12 p40(-)) mice were generated by crossing T3(b)-IL-12 p40 transgenic mice and IL- 10(-/-) mice. At 8 weeks of age, IL- 12 p40(+) mice did not show any clinical manifestations of colitis. The colon length of IL- 12 p40(-) mice became shorter than that of IL- 12 p40(+) mice. The histological score of IL- 12 p40(+) mice was lower. Interferon-gamma ( IFN-gamma) production was suppressed in both the mesenteric lymph node cell culture and colon tissue culture of IL- 12 p40(+) mice. There was no significant difference in IL- 4 production and tumor necrosis factor-alpha (TNF-alpha) production between the two groups. These results show that overexpression of IL- 12 p40 in intestinal epithelia prevents enterocolitis in IL-10(-/-) mice by suppressing IFN-gamma production, and suggest a potential clinical application of IL-12 p40 for Crohn's disease. Furthermore, these results also suggest that local gene transduction in the intestinal epithelium may be a potent therapeutic approach for Crohn's disease.