TY - JOUR
T1 - Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease
AU - Kanai, Takanori
AU - Watanabe, Mamoru
AU - Okazawa, Akira
AU - Sato, Toshiro
AU - Yamazaki, Motomi
AU - Okamoto, Susumu
AU - Ishii, Hiromasa
AU - Totsuka, Teruji
AU - Iiyama, Ryoichi
AU - Okamoto, Ryuichi
AU - Ikeda, Masao
AU - Kurimoto, Masashi
AU - Takeda, Kiyoshi
AU - Akira, Shizuo
AU - Hibi, Toshifumi
N1 - Funding Information:
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, and Keio University Medical Science Fund, Tokyo, Japan.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1053/gast.2001.28021
DO - 10.1053/gast.2001.28021
M3 - Article
C2 - 11606501
AN - SCOPUS:0034800289
SN - 0016-5085
VL - 121
SP - 875
EP - 888
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -
