Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice

Takahiro Ishikura, Takanori Kanai, Koji Uraushihara, Ryoichi Iiyama, Shin Makita, Teruji Totsuka, Motomi Yamazaki, Taisuke Sawada, Tetsuya Nakamura, Tatsuya Miyata, Tetsuji Kitahora, Toshifumi Hibi, Tomoaki Hoshino, Mamoru Watanabe

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Abstract

Background and Aim: 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.

Original languageEnglish
Pages (from-to)960-969
Number of pages10
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume18
Issue number8
DOIs
Publication statusPublished - 2003 Aug 1
Externally publishedYes

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Keywords

  • Dextran sulfate sodium-induced colitis
  • Interleukin-18
  • Interleukin-18 transgenic mice
  • Macrophage

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Ishikura, T., Kanai, T., Uraushihara, K., Iiyama, R., Makita, S., Totsuka, T., Yamazaki, M., Sawada, T., Nakamura, T., Miyata, T., Kitahora, T., Hibi, T., Hoshino, T., & Watanabe, M. (2003). Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice. Journal of Gastroenterology and Hepatology (Australia), 18(8), 960-969. https://doi.org/10.1046/j.1440-1746.2003.03097.x