Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease

Takanori Kanai, Mamoru Watanabe, Akira Okazawa, Toshiro Sato, Motomi Yamazaki, Susumu Okamoto, Hiromasa Ishii, Teruji Totsuka, Ryoichi Iiyama, Ryuichi Okamoto, Masao Ikeda, Masashi Kurimoto, Kiyoshi Takeda, Shizuo Akira, Toshifumi Hibi

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150 Citations (Scopus)

Abstract

Background & Aims: Crohn's disease (CD) is associated with an increased number of infiltrating macrophages, which release a variety of proinflammatory cytokines. Interleukin (IL)-18 has been implicated in the modulation of mucosal CD4+ T cells towards Th1 responses, which are implicated in the pathogenesis of CD. Here we assess the role of macrophages and of IL-18 in the murine model of intestinal inflammation that mimics the immunologic characteristics of human CD. Methods: Colitis was induced in C57BL/6 mice immunized with 2,4,6-trinitrobenzene sulfonic acid (TNBS) followed by rectal administration of TNBS in ethanol. Mice were treated with either an antibody directed against macrophages conjugated to the ribosome-inactivating protein saporin (anti-Mac-1-saporin) or with a neutralizing antibody against IL-18. In addition, we assessed whether an identical TNBS immunization/challenge protocol could induce colitis in IL-18-/- mice. Results: The colonic mucosa of TNBS-treated mice was marked by infiltration of Mac-1-positive macrophages and up-regulation of IL-18. The administration of the anti-Mac-1-saporin antibody or the neutralizing anti-IL-18 antibody resulted in a dramatic attenuation of mucosal inflammation in this model. In addition, TNBS was unable to induce significant colitis in the IL-18-/- mice. Conclusions: Our data underscore the pivotal role of macrophages, and the macrophage-derived IL-18, in the establishment of TNBS-induced colitis in mice. Our results highlight the potential use of therapy directed against IL-18 in the treatment of patients with CD.

Original languageEnglish
Pages (from-to)875-888
Number of pages14
JournalGastroenterology
Volume121
Issue number4
DOIs
Publication statusPublished - 2001 Jan 1

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Kanai, T., Watanabe, M., Okazawa, A., Sato, T., Yamazaki, M., Okamoto, S., Ishii, H., Totsuka, T., Iiyama, R., Okamoto, R., Ikeda, M., Kurimoto, M., Takeda, K., Akira, S., & Hibi, T. (2001). Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterology, 121(4), 875-888. https://doi.org/10.1053/gast.2001.28021