Yoshitaka Ueno

Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes.

The interaction of mucosal lymphocytes and intestinal epithelial cells is thought to be important in regulating immune response in the intestinal mucosa, but conclusive evidence is limited. Here we demonstrate the expression of IL-7 mRNA in human intestinal mucosa by combined reverse transcription PCR and Southern blot hybridization. Immunohistochemistry and in situ hybridization confirm the presence of IL-7 in intestinal epithelial cells, especially in epithelial goblet cells. Moreover, IL-7 receptor expression in mucosal lymphocytes is demonstrated by immunohistochemistry and in situ hybridization, as well as by Southern blot and flow cytometric analysis of freshly isolated lamina propria lymphocytes. In contrast, IL-7 receptor could not be detected in the cell surface of freshly isolated PBLs. The functional activity of IL-7 receptor is demonstrated by the utility of recombinant IL-7 to stimulate the growth of lamina propria lymphocytes, and conversely inhibit CD3-dependent proliferation of these cells. In contrast, IL-7 caused no significant increase in DNA synthesis and cell numbers when added to PBLs. These findings suggest that human intestinal epithelial cells and epithelial goblet cells produce IL-7, and locally produced IL-7 may serve as a potent regulatory factor for intestinal mucosal lymphocytes.

The serum factor from patients with ulcerative colitis that induces T cell proliferation in the mouse thymus is interleukin-7

The disturbance of immune regulatory T cells is related to the pathogenesis of ulcerative colitis. Here we demonstrated and characterized the serum factor from ulcerative colitis patients that induced proliferation of intrathymic T cells. The factor isolated from the patient sera by a combination of gel filtration and anion-exchange chromatography induced proliferation of CD4+CD8− intrathymic T cells in the organ-cultured embryonic mouse thymus. Purification and amino acid sequence analysis of the serum factor demonstrated that the N-terminal 12 sequence was homologous to that of interleukin-7. SDS-PAGE and Western blot confirmed that purified serum factor was interleukin-7. Enzyme immunoassay demonstrated that the serum interleukin-7 concentration was significantly increased in the patients. PCR and Southern blot hybridization demonstrated that interleukin-7 mRNA expression was increased in the thymus tissues from patients but decreased in the colonic mucosa. Since interleukin-7 is a crucial cytokine for proliferation and differentiation of T cells in the thymus, the present study indicates that interleukin-7 may contribute to the disturbance of immune regulatory T cells in ulcerative colitis.

Mucosal IL-7-mediated immune responses in chronic colitis-IL-7 transgenic mouse model

We have demonstrated that intestinal epithelial cells produce interleukin-7 (IL-7) and IL-7 serves as a regulatory factor for proliferation of mucosal lymphocytes. To clarify the mechanism by which locally produced IL-7 regulates mucosal lymphocytes and the role of mucosal IL-7 in colonic inflammation, we investigated IL-7 transgenic (IL-7 Tg) mice and demonstrated that IL-7 Tg mice developed acute and chronic colitis with histopathological similarity to ulcerative colitis in humans. In concert with our recent findings that IL-7 stimulates the proliferation of inactivated mucosal lymphocytes but eliminates activated lymphocytes in the inflamed mucosa of human ulcerative colitis. These findings suggest that chronic inflammation in the colonie mucosa is mediated by dysregulation of epithelial cell-derived IL-7 system.

Intestinal Epithelial Cell-Derived Interleukin-7 as a Regulatory Factor for Intestinal Mucosal Lymphocytes

Publisher Summary Recent studies have demonstrated that interactions between mucosal lymphocytes and intestinal epithelial cells are crucial for maintaining mucosal immunity. The mucosal lymphocytes may serve a critical role in the mucosal immune system by providing immune surveillance of epithelial cells. Although recent studies have shown that cytokines released from mucosal mononuclear cells may affect intestinal epithelial cell differentiation, the signals originating from epithelial cells that may regulate mucosal lymphocytes are yet to be defined. It has been reported that mucosal lymphocytes proliferate minimally to mitogens or stimulation through the CD3 pathway. This in vitro hyporesponsiveness of mucosal lymphocytes is supposed to be due to the absence of essential growth factor. Interleukin-7 (IL-7) is a stromal cell-derived pleiotropic cytokine with lymphoid precursor cell growth-promoting activity. The recent studies have demonstrated IL-7 mRNA expression and IL-7 protein production in the intestinal epithelial cells. These results, in concert with the findings that IL-7 receptors are expressed by mucosal lymphocytes, suggest that IL-7 regulates the proliferation of the intestinal mucosal lymphocytes. This chapter reviews the intestinal epithelial cell-derived IL-7 as a regulatory factor for the intestinal mucosal lymphocytes.