Gastroenterology

Gastroenterology

Volume 119, Issue 6, December 2000, Pages 1514-1523
Gastroenterology

Alimentary Tract
Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease,☆☆

https://doi.org/10.1053/gast.2000.20260Get rights and content

Abstract

Background & Aims: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4+ T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4+ T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes. Methods: Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity. Results: The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18+CD68+ macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. IL-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls. Conclusions: These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.

GASTROENTEROLOGY 2000;119:1514-1523

Section snippets

Patients and samples

Serum samples were obtained from 21 patients with CD, 23 patients with UC, and 15 healthy controls. Human sera were separated by Vacutainer (Becton Dickinson, Bedford, MA).

Mucosal samples were obtained from the inflamed areas and noninflamed areas of intestinal mucosa of 29 patients with CD (16 surgical specimens and 13 biopsy specimens; 19 inflamed and 10 noninflamed specimens). The primary site of involvement was ileal in 12, ileocolonic in 10, and colonic in 7 patients. Controls included (1)

Serum IL-18 concentration

As shown in Figure 1A, serum IL-18 concentration in normal controls ranged from 0 to 139.0 pg/mL, with an average of 37.7 pg/mL, whereas the IL-18 concentration in the sera of CD patients was significantly (P < 0.001) higher, ranging between 41.0 and 240.3 pg/mL, (average, 122.2 pg/mL).

. (A) Serum IL-18 concentrations in normal controls (15 cases), patients with CD (21 cases), and patients with UC (23 cases) were measured using a human IL-18–specific ELISA. Serum IL-18 concentration was

Discussion

IL-18 has been shown to contribute to Th1-mediated immune responses and chronic inflammation. However, the role of IL-18 in mucosal immune responses and intestinal inflammation is not fully understood. In this study we show that serum IL-18 levels are significantly higher in CD, which is a human Th1-mediated chronic inflammatory bowel disease. In contrast, serum IL-18 concentration was not statistically higher in UC compared with normal controls. This is the first study to describe increased

Acknowledgements

The authors thank Prof. Daniel Podolsky for critical comments, Dr. Hiromichi Ishikawa for helpful discussion; Drs. Yasuo Hosoda, Motomi Yamazaki, Haruhiko Ogata, and Yasushi Iwao for technical assistance; Drs. Masahiko Watanabe, Akira Tsuyuki, Masaki Kitajima, and Akira Sugita for providing the specimens; and Miss Reiko Fujisaki for manuscript preparation.

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    Address requests for reprints to: Toshifumi Hibi, M.D., Keio Cancer Center, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. e-mail: [email protected]; fax: (81) 3-3357-6156.

    ☆☆

    Supported in part by grants-in-aid from the Japanese Ministry of Education, Culture and Science; the Japanese Ministry of Health and Welfare; Chiyoda Mutual Life Foundation; Japan Health Sciences Foundation; Keio University; and Keio University Medical Fund.

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