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.
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 humanCD. 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.
Authors: Roni Nowarski; Ruaidhrí Jackson; Nicola Gagliani; Marcel R de Zoete; Noah W Palm; Will Bailis; Jun Siong Low; Christian C D Harman; Morven Graham; Eran Elinav; Richard A Flavell Journal: Cell Date: 2015-12-03 Impact factor: 41.582
Authors: D Struck; I Frank; S Enders; U Steinhoff; C Schmidt; A Stallmach; O Liesenfeld; M M Heimesaat Journal: Eur J Microbiol Immunol (Bp) Date: 2012-09-10
Authors: Akhil Maheshwari; David R Kelly; Teodora Nicola; Namasivayam Ambalavanan; Sunil K Jain; Joanne Murphy-Ullrich; Mohammad Athar; Masako Shimamura; Vineet Bhandari; Charles Aprahamian; Reed A Dimmitt; Rosa Serra; Robin K Ohls Journal: Gastroenterology Date: 2010-09-24 Impact factor: 22.682
Authors: A Okazawa; T Kanai; K Nakamaru; T Sato; N Inoue; H Ogata; Y Iwao; M Ikeda; T Kawamura; S Makita; K Uraushihara; R Okamoto; M Yamazaki; M Kurimoto; H Ishii; M Watanabe; T Hibi Journal: Clin Exp Immunol Date: 2004-05 Impact factor: 4.330
Authors: Hon-Wai Koon; You Sun Kim; Hua Xu; Aatish Kumar; Dezheng Zhao; Iordanes Karagiannides; Paul R Dobner; Charalabos Pothoulakis Journal: Proc Natl Acad Sci U S A Date: 2009-05-14 Impact factor: 11.205