Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement

Akira Okazawa, Takanori Kanai, Mamoru Watanabe, Motomi Yamazaki, Nagamu Inoue, Masao Ikeda, Masashi Kurimoto, Hiromasa Ishii, Toshifumi Hibi

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) β1, β2, and IL-18Rα in LPLs was analyzed by flow cytometry. The functional activity of IL-12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-γ production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rβ2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-γ production and IL-2Rα expression when exposed to both IL-12 and IL-18, but neither IL-12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Rα monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Rα expression in LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.

Original languageEnglish
Pages (from-to)3108-3117
Number of pages10
JournalAmerican Journal of Gastroenterology
Volume97
Issue number12
DOIs
Publication statusPublished - 2002 Dec 1

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Interleukin-18
Interleukin-12
T-Cell Antigen Receptor
Crohn Disease
Mucous Membrane
Lymphocytes
Inflammation
Interleukins
Interferons
Interleukin-2
Interleukin-12 Receptors
Macrophages
Th1 Cells
Intestinal Mucosa
Interleukin-1
Flow Cytometry
Up-Regulation
Epithelial Cells
Monoclonal Antibodies
Maintenance

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement. / Okazawa, Akira; Kanai, Takanori; Watanabe, Mamoru; Yamazaki, Motomi; Inoue, Nagamu; Ikeda, Masao; Kurimoto, Masashi; Ishii, Hiromasa; Hibi, Toshifumi.

In: American Journal of Gastroenterology, Vol. 97, No. 12, 01.12.2002, p. 3108-3117.

Research output: Contribution to journalArticle

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title = "Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement",
abstract = "OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) β1, β2, and IL-18Rα in LPLs was analyzed by flow cytometry. The functional activity of IL-12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-γ production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rβ2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-γ production and IL-2Rα expression when exposed to both IL-12 and IL-18, but neither IL-12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Rα monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Rα expression in LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.",
author = "Akira Okazawa and Takanori Kanai and Mamoru Watanabe and Motomi Yamazaki and Nagamu Inoue and Masao Ikeda and Masashi Kurimoto and Hiromasa Ishii and Toshifumi Hibi",
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T1 - Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement

AU - Okazawa, Akira

AU - Kanai, Takanori

AU - Watanabe, Mamoru

AU - Yamazaki, Motomi

AU - Inoue, Nagamu

AU - Ikeda, Masao

AU - Kurimoto, Masashi

AU - Ishii, Hiromasa

AU - Hibi, Toshifumi

PY - 2002/12/1

Y1 - 2002/12/1

N2 - OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) β1, β2, and IL-18Rα in LPLs was analyzed by flow cytometry. The functional activity of IL-12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-γ production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rβ2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-γ production and IL-2Rα expression when exposed to both IL-12 and IL-18, but neither IL-12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Rα monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Rα expression in LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.

AB - OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) β1, β2, and IL-18Rα in LPLs was analyzed by flow cytometry. The functional activity of IL-12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-γ production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rβ2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-γ production and IL-2Rα expression when exposed to both IL-12 and IL-18, but neither IL-12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Rα monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Rα expression in LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD.

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