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

Background & Aims: T-cell receptor α mutant (TCRα −/−) mice spontaneously develop colitis resembling ulcerative colitis (UC). The role of interleukin (IL)-4 and interferon (IFN)-γ in the pathogenesis of colitis was examined by creating IL-4– or IFN-γ–deficient TCRα −/− mice. Methods: Double-mutant mice were created by crossing TCRα −/− mice with IL-4– or IFN-γ–deficient mice. Colitis was grossly and histologically assessed at 6 months of age, and the cytokine profile in the mesenteric lymph nodes and colons in these mice was analyzed. Results: The lack of IL-4 dramatically suppressed the development of colitis at 6 months of age. In contrast, IFN-γ −/− × TCRα −/− mice developed colitis similar to that present in TCRα −/− mice. Furthermore, proliferation of colonic epithelial cells was markedly increased in TCRα −/− mice and IFN-γ −/− × TCRα −/− mice compared with IL-4 −/− × TCRα −/− mice. Continuous administration of recombinant IL-4 led to increased colonic epithelial cell proliferation in IL-4 −/− × TCRα −/− mice. Conclusions: IL-4 plays an important role in the development of colitis in TCRα −/− mice. In contrast, severe colitis in TCRα −/− mice can develop in the absence of IFN-γ. GASTROENTEROLOGY 1999;116:320-326