Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice.
OBJECTIVE
The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined.


METHODS
Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry.


RESULTS
The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg.


CONCLUSIONS
These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice.
Ishikura
Takahiro
T
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kanai
Takanori
T
Uraushihara
Koji
K
Iiyama
Ryoichi
R
Makita
Shin
S
Totsuka
Teruji
T
Yamazaki
Motomi
M
Sawada
Taisuke
T
Nakamura
Tetsuya
T
Miyata
Tatsuya
T
Kitahora
Tetsuji
T
Hibi
Toshifumi
T
Hoshino
Tomoaki
T
Watanabe
Mamoru
M
D000704:Analysis of Variance; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005434:Flow Cytometry; D020382:Interleukin-18 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D020382:Interleukin-18; D016264:Dextran Sulfate