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 language | English |
|---|---|
| Pages (from-to) | 875-888 |
| Number of pages | 14 |
| Journal | Gastroenterology |
| Volume | 121 |
| Issue number | 4 |
| Publication status | Published - 2001 |
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ASJC Scopus subject areas
- Gastroenterology
Cite this
Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. / Kanai, Takanori; Watanabe, Mamoru; Okazawa, Akira; Sato, Toshiro; Yamazaki, Motomi; Okamoto, Susumu; Ishii, Hiromasa; Totsuka, Teruji; Iiyama, Ryoichi; Okamoto, Ryuichi; Ikeda, Masao; Kurimoto, Masashi; Takeda, Kiyoshi; Akira, Shizuo; Hibi, Toshifumi.
In: Gastroenterology, Vol. 121, No. 4, 2001, p. 875-888.Research output: Contribution to journal › Article
}
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
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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M3 - Article
VL - 121
SP - 875
EP - 888
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 4
ER -