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J. Exp. Med., Volume 187, Number 3, February 2, 1998 389-402

Interleukin 7 Transgenic Mice Develop Chronic Colitis with Decreased Interleukin 7 Protein Accumulation in the Colonic Mucosa

By Mamoru Watanabe,* Yoshitaka Ueno,Dagger Tomoharu Yajima,Dagger Susumu Okamoto,Dagger Tatsuhiko Hayashi,Dagger Motomi Yamazaki,* Yasushi Iwao,Dagger Hiromasa Ishii,Dagger Sonoko Habu, Masahiro Uehira,** Hirofumi Nishimoto,** Hiromichi Ishikawa,§ Jun-ichi Hata,par and Toshifumi Hibi*

From the * Keio Cancer Center, Dagger  the Department of Internal Medicine, § the Department of Microbiology, and par  the Department of Pathology, School of Medicine, Keio University, Tokyo 160, Japan;  the Department of Immunology, School of Medicine, Tokai University, Isehara 259-11, Japan; and the ** Shionogi Institute for Medical Science, Osaka 553, Japan

We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRalpha promoter developed chronic colitis in concert with the expression of SRalpha /IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4-12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell-depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor gamma /delta T cells and CD8alpha /alpha cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell-derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.


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