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Systemic, but Not Intestinal, IL-7 Is Essential for the Persistence of Chronic Colitis¹

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

We previously demonstrated that IL-7 is produced by intestinal goblet cells and is essential for the persistence of colitis. It is well known, however, that goblet cells are decreased or depleted in the chronically inflamed mucosa of animal colitis models or human inflammatory bowel diseases. Thus, in this study, we assess whether intestinal IL-7 is surely required for the persistence of colitis using a RAG-1/2^–/– colitis model induced by the adoptive transfer of CD4⁺CD45RB^high T cells in combination with parabiosis system. Surprisingly, both IL-7^–/– x RAG-1^–/– and IL-7^+/+ x RAG-1^–/– host mice developed colitis 4 wk after parabiosis to a similar extent of colitic IL-7^+/+ x RAG-1^–/– donor mice that were previously transferred with CD4⁺CD45RB^high T cells. Of note, although the number of CD4⁺ T cells recovered from the spleen or the bone marrow of IL-7^–/– x RAG-1^–/– host mice was significantly decreased compared with that of IL-7^+/+ x RAG-1^–/– host mice, an equivalent number of CD4⁺ T cells was recovered from the lamina propria of both mice, indicating that the expansion of CD4⁺ T cells in the spleen or in the bone marrow is dependent on IL-7, but not in the lamina propria. Development of colitis was never observed in parabionts between IL-7^+/+ x RAG-1^–/– host and noncolitic IL-7^–/– x RAG-1^–/– donor mice that were transferred with CD4⁺CD45RB^high T cells. Collectively, systemic, but not intestinal, IL-7 is essential for the persistence of colitis, suggesting that therapeutic approaches targeting the systemic IL-7/IL-7R signaling pathway may be feasible in the treatment of inflammatory bowel diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by grants-in-aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research and Creative Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology; the Japanese Ministry of Health, Labor and Welfare; the Japan Medical Association; Foundation for Advancement of International Science; Terumo Life science Foundation; Ohyama Health Foundation; Yakult Bio-Science Foundation; and Research Fund of Mitsukoshi Health and Welfare Foundation.

² Address correspondence and reprint requests to Dr. Takanori Kanai, Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: taka.gast{at}tmd.ac.jp

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; BM, bone marrow; LP, lamina propria; SP, spleen; Tg, transgenic; IEL, intraepithelial cell; HPF, high power field; DAPI, 4', 6'-diamidino-2-phenylindole; LN, lymph node.