A Mizoguchi1, E Mizoguchi, A K Bhan. 1. Immunopathology Unit, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract
BACKGROUND & AIMS: T-cell receptor alpha mutant (TCRalpha-/-) mice spontaneously develop colitis resembling ulcerative colitis (UC). The role of interleukin (IL)-4 and interferon (IFN)-gamma in the pathogenesis of colitis was examined by creating IL-4- or IFN-gamma-deficient TCRalpha-/- mice. METHODS: Double-mutant mice were created by crossing TCRalpha-/- mice with IL-4- or IFN-gamma-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-gamma-/- x TCRalpha-/- mice developed colitis similar to that present in TCRalpha-/- mice. Furthermore, proliferation of colonic epithelial cells was markedly increased in TCRalpha-/- mice and IFN-gamma-/- x TCRalpha-/- mice compared with IL-4(-/-) x TCRalpha-/- mice. Continuous administration of recombinant IL-4 led to increased colonic epithelial cell proliferation in IL-4(-/-) x TCRalpha-/- mice. CONCLUSIONS: IL-4 plays an important role in the development of colitis in TCRalpha-/- mice. In contrast, severe colitis in TCRalpha-/- mice can develop in the absence of IFN-gamma.
BACKGROUND & AIMS: T-cell receptor alpha mutant (TCRalpha-/-)mice spontaneously develop colitis resembling ulcerative colitis (UC). The role of interleukin (IL)-4 and interferon (IFN)-gamma in the pathogenesis of colitis was examined by creating IL-4- or IFN-gamma-deficient TCRalpha-/-mice. METHODS: Double-mutant mice were created by crossing TCRalpha-/-mice with IL-4- or IFN-gamma-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-gamma-/- x TCRalpha-/-mice developed colitis similar to that present in TCRalpha-/-mice. Furthermore, proliferation of colonic epithelial cells was markedly increased in TCRalpha-/-mice and IFN-gamma-/- x TCRalpha-/-mice compared with IL-4(-/-) x TCRalpha-/-mice. Continuous administration of recombinant IL-4 led to increased colonic epithelial cell proliferation in IL-4(-/-) x TCRalpha-/-mice. CONCLUSIONS:IL-4 plays an important role in the development of colitis in TCRalpha-/-mice. In contrast, severe colitis in TCRalpha-/-mice can develop in the absence of IFN-gamma.
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Authors: Michael J Rosen; Rebekah Karns; Jefferson E Vallance; Ramona Bezold; Amanda Waddell; Margaret H Collins; Yael Haberman; Phillip Minar; Robert N Baldassano; Jeffrey S Hyams; Susan S Baker; Richard Kellermayer; Joshua D Noe; Anne M Griffiths; Joel R Rosh; Wallace V Crandall; Melvin B Heyman; David R Mack; Michael D Kappelman; James Markowitz; Dedrick E Moulton; Neal S Leleiko; Thomas D Walters; Subra Kugathasan; Keith T Wilson; Simon P Hogan; Lee A Denson Journal: Gastroenterology Date: 2017-01-26 Impact factor: 22.682