Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease.
OBJECTIVE
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.
Kanai
T
T
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Watanabe
M
M
Okazawa
A
A
Sato
T
T
Yamazaki
M
M
Okamoto
S
S
Ishii
H
H
Totsuka
T
T
Iiyama
R
R
Okamoto
R
R
Ikeda
M
M
Kurimoto
M
M
Takeda
K
K
Akira
S
S
Hibi
T
T
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D003424:Crohn Disease / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014302:Trinitrobenzenesulfonic Acid
D000906:Antibodies; D020382:Interleukin-18; D014302:Trinitrobenzenesulfonic Acid