title: Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa.
abstract: 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.
authors.affiliation: Keio Cancer Center, School of Medicine, Keio University, Tokyo 160, Japan. mamoru@mc.med.keio.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Ueno
authors.forename: T
authors.initials: T
authors.lastname: Yajima
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Iwao
authors.forename: H
authors.initials: H
authors.lastname: Ishii
authors.forename: S
authors.initials: S
authors.lastname: Habu
authors.forename: M
authors.initials: M
authors.lastname: Uehira
authors.forename: H
authors.initials: H
authors.lastname: Nishimoto
authors.forename: H
authors.initials: H
authors.lastname: Ishikawa
authors.forename: J
authors.initials: J
authors.lastname: Hata
authors.forename: T
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015139:Blotting, Southern; D003092:Colitis / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D020395:Receptors, Interleukin-7; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D015851:Interleukin-7; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7