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 - 2001/1/1
Y1 - 2001/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=0034800289&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034800289&partnerID=8YFLogxK
U2 - 10.1053/gast.2001.28021
DO - 10.1053/gast.2001.28021
M3 - Article
C2 - 11606501
AN - SCOPUS:0034800289
VL - 121
SP - 875
EP - 888
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 4
ER -