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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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

Fingerprint

Interleukin-18
Colitis
Transgenic Mice
Macrophages
Dextran Sulfate
Mucous Membrane
T-Lymphocytes
Crohn Disease
Lymph Nodes
Inflammation
Flow Cytometry
Colon

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice. / Ishikura, Takahiro; Kanai, Takanori; Uraushihara, Koji; Iiyama, Ryoichi; Makita, Shin; Totsuka, Teruji; Yamazaki, Motomi; Sawada, Taisuke; Nakamura, Tetsuya; Miyata, Tatsuya; Kitahora, Tetsuji; Hibi, Toshifumi; Hoshino, Tomoaki; Watanabe, Mamoru.

In: Journal of Gastroenterology and Hepatology (Australia), Vol. 18, No. 8, 01.08.2003, p. 960-969.

Research output: Contribution to journalArticle

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), vol. 18, no. 8, pp. 960-969. https://doi.org/10.1046/j.1440-1746.2003.03097.x
Ishikura, Takahiro ; Kanai, Takanori ; Uraushihara, Koji ; Iiyama, Ryoichi ; Makita, Shin ; Totsuka, Teruji ; Yamazaki, Motomi ; Sawada, Taisuke ; Nakamura, Tetsuya ; Miyata, Tatsuya ; Kitahora, Tetsuji ; Hibi, Toshifumi ; Hoshino, Tomoaki ; Watanabe, Mamoru. / Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice. In: Journal of Gastroenterology and Hepatology (Australia). 2003 ; Vol. 18, No. 8. pp. 960-969.
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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.",
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T1 - Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice

AU - Ishikura, Takahiro

AU - Kanai, Takanori

AU - Uraushihara, Koji

AU - Iiyama, Ryoichi

AU - Makita, Shin

AU - Totsuka, Teruji

AU - Yamazaki, Motomi

AU - Sawada, Taisuke

AU - Nakamura, Tetsuya

AU - Miyata, Tatsuya

AU - Kitahora, Tetsuji

AU - Hibi, Toshifumi

AU - Hoshino, Tomoaki

AU - Watanabe, Mamoru

PY - 2003/8/1

Y1 - 2003/8/1

N2 - 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.

AB - 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.

KW - Dextran sulfate sodium-induced colitis

KW - Interleukin-18

KW - Interleukin-18 transgenic mice

KW - Macrophage

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