The critical role of interleukin 4 but not interferon gamma in the pathogenesis of colitis in T-cell receptor alpha mutant mice

Background & Aims: T-cell receptor or mutant (TCR alpha(-/-)) mice spontane ously develop colitis resembling ulcerative colitis (UC). The role of inter leukin (IL)-4 and interferon (IFN)-gamma in the pathogenesis of colitis was examined by creating IL-4- or IFN-gamma-deficient TCR alpha(-/-) mice. Met hods: Double-mutant mice were created by crossing TCR alpha(-/-) mice with IL-4- or IFN-gamma-deficient mice. Colitis was grossly and histologically a ssessed at 6 months of age, and the cytokine profile in the mesenteric lymp h nodes and colons in these mice was analyzed. Results: The lack of IL-4 dr amatically suppressed the development of colitis at 6 months of age. In con trast, IFN-gamma(-/-) x TCR alpha(-/-) mice developed colitis similar to th at present in TCR alpha(-/-) mice. Furthermore, proliferation of colonic ep ithelial cells was markedly increased in TCR alpha(-/-) mice and IFN-gamma( -/-) x TCR alpha(-/-) mice compared with IL-4(-/-) x TCR alpha(-/-) mice. C ontinuous administration of recombinant IL-4 led to increased colonic epith elial cell proliferation in IL-4(-/-) x TCR alpha(-/-) mice. Conclusions: I L-4 plays an important role in the development of colitis in TCR alpha(-/-) mice. In contrast, severe colitis in TCR alpha(-/-) mice can develop in th e absence of IFN-gamma.