INTERLEUKIN-7 TRANSGENIC MICE DEVELOP CHRONIC COLITIS WITH DECREASED INTERLEUKIN-7 PROTEIN ACCUMULATION IN THE COLONIC MUCOSA

We have demonstrated that intestinal epithelial cells produce interleu kin 7 (IL-7), and IL-7 serves as a potent regulatory factor for prolif eration of intestinal mucosal lymphocytes expressing functional IL-7 r eceptor. To clarify the mechanism by which locally produced IL-7 regul ates the mucosal lymphocytes, we investigated IL-7 transgenic mice. He re we report that transgenic mice expressing murine IL-7 cDNA driver b y the SR alpha promoter developed chronic colitis in concert with the expression of SR alpha/IL-7 transgene in the colonic mucosa. IL-7 tran sgenic but not littermate mice developed chronic colitis at 4-12 wk of age, with histopathological similarity to ulcerative colitis in human s. Southern blot hybridization and competitive PCR demonstrated that t he expression of IL-7 messenger RNA was increased in the colonic mucos al lymphocytes but not in the colonic epithelial cells. IL-7 protein a ccumulation was decreased in the goblet cell-depleted colonic epitheli um 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 ana lysis demonstrated that CD4(+) intraepithelial T cells were increased, but T cell receptor gamma/delta T cells and CD8 alpha/alpha. cells we re not increased in the area of chronic inflammation. Increased IL-7 r eceptor expression in mucosal lymphocytes was demonstrated in the tran sgenic mice. These findings suggest that chronic inflammation in the c olonic mucosa may be mediated by dysregulation of colonic epithelial c ell-derived IL-7, and this murine model of chronic colitis may contrib ute to the understanding of the pathogenesis of human inflammatory bow el disease.