Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa

• Published in: The Journal of experimental medicine Vol. 187; no. 3; pp. 389 - 402
• Main Authors: Watanabe, M, Ueno, Y, Yajima, T, Okamoto, S, Hayashi, T, Yamazaki, M, Iwao, Y, Ishii, H, Habu, S, Uehira, M, Nishimoto, H, Ishikawa, H, Hata, J, Hibi, T
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 02.02.1998
• Subjects: Animals; Antigens, CD - immunology; Antigens, CD - metabolism; Blotting, Southern; Colitis - etiology; Colitis - genetics; Colitis - immunology; Colitis - pathology; Cytokines - metabolism; Disease Models, Animal; Flow Cytometry; Gene Expression Regulation - genetics; Humans; Immunohistochemistry; Inflammation - immunology; Interleukin-7 - genetics; Interleukin-7 - metabolism; Interleukin-7 - pharmacology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Lymphocytes - immunology; Lymphocytes - metabolism; Mice; Mice, Transgenic; Promoter Regions, Genetic - genetics; Receptors, Interleukin - metabolism; Receptors, Interleukin-7; RNA, Messenger - analysis; RNA, Messenger - metabolism; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.187.3.389

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.