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

From the ^* Keio Cancer Center, the Department of Internal Medicine, the Department of Microbiology, and ^|| 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 SR promoter developed chronic colitis in concert with the expression of SR/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 / T cells and CD8/ 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.

The authors would like to express special thanks to Professors Daniel Podolsky, Lloyd Mayer, and Sadakazu Aiso for critical comments; Drs. Noriaki Watanabe, Yasuo Hosoda, Nagamu Inoue, and Hiromasa Takaishi for technical assistance; and Miss Reiko Fujisaki for manuscript preparation.

¹ Abbreviations used in this paper: G3PDH, glyceraldehyde 3-phosphate dehydrogenase; IEL, intraepithelial lymphocyte; LPL, lamina propria lymphocyte; mRNA, messenger RNA; RT-PCR, reverse transcriptase PCR.

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