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 SRα promoter developed chronic colitis in concert with the expression of SRα/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 γ/δ T cells and CD8α/α 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.

IL-7 Is Essential for the Development and the Persistence of Chronic Colitis

“…First, IL-7 transgenic mice developed chronic colitis that mimicked histopathological characteristics of human IBD (12). As chronic colitis developed, IL-7 transgenic mice showed significant infiltration of IL-7R high CD4 ϩ T cells in the colonic LP.…”

IL-7 receptor α blockade, an off-switch for autoreactive T cells

“…Although this connection bears great therapeutic potential, it also carries undeniable risks. Just as IL-7 treatment for chronic viral infections bears the risk for developing autoimmune diseases by thwarting immune regulation (8)(9)(10), blockade of the IL-7R might increase the susceptibility for certain infections or even cancer in humans. Therefore, the degree to which IL-7Rα actually induces immunosuppression, if at all, needs to be carefully investigated in the future.…”

“…In both cases, therapeutic administration of recombinant IL-7 enhanced the antigen-specific T-cell responses by amplifying survival and effector mechanisms and counteracting several inhibitory pathways, such as PD-1 (7,8). However, IL-7 has the unfortunate ability to promote the emergence of autoreactive T cells, and thus can be associated with the development of autoimmune diseases (9,10). The importance of IL-7 in the development of autoimmune disorders is further underlined by observations from genome-wide association studies that identified genetic variations of the IL-7Rα chain as risk factors for the development of T1D and multiple sclerosis (11,12).…”

IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice

“…2,3 Recently, various mice models of intestinal inflammation mediated by a Th1 response have been established. These mice models, including interleukin (IL)-2), 4,5 IL-10, and Stat3 6 -deficient mice, IL-7 transgenic mice, 7 Tnf DARE mice, 8,9 senescence accelerated mice P1/Yit strain, 10,11 2,4,6-trinitrobenzenesulfonic acid (TNBS)-treated mice, 12 and CD4 þ CD45RB high T cell transferred SCID mice, 13,14 have provided new insight concerning the intestinal inflammation of Crohn's disease and its pathogenesis. The methods by which the inflammation is prevented in these models could lead to new cytokine therapies for Crohn's disease.…”