Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria

Nobuhiko Kamada, Tadakazu Hisamatsu, Susumu Okamoto, Toshiro Sato, Katsuyoshi Matsuoka, Kumiko Arai, Takaaki Nakai, Akira Hasegawa, Nagamu Inoue, Noriaki Watanabe, Kiyoko S. Akagawa, Toshifumi Hibi

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Abstract

Disorders in enteric bacteria recognition by intestinal macrophages (Mφ) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of Mφ in intestinal inflammation by using an IL-10-deficient (IL-10-/-) mouse colitis model. GM-CSF-induced bone marrow-derived Mφ (GM-Mφ) and M-CSF-induced bone marrow-derived Mφ (M-Mφ) were generated from bone marrow CD11b+ cells. M-Mφ from IL-10-/- mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-Mφ from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-Mφ was not significantly different between WT and IL-10-/- mice. In ex vivo experiments, cytokine production ability of colonic lamina propria Mφ (CLPMφ) but not splenic Mφ from WT mice was similar to that of M-Mφ, and CLPMφ but not splenic Mφ from IL-10-/- mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from IL-10-/- from IL-10-/- mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPMφ and M-Mφ act as anti-inflammatory Mφ and suppress excess inflammation induced by bacteria in WT mice. In IL-10 -/- mice, however, such Mφ subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal Mφ may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal Mφ to gut flora relationship in the development of colitis in IL-10-/- mice.

Original languageEnglish
Pages (from-to)6900-6908
Number of pages9
JournalJournal of Immunology
Volume175
Issue number10
Publication statusPublished - 2005 Nov 15

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Interleukin-23
Colitis
Interleukin-12
Interleukin-10
Macrophages
Bacteria
Bone Marrow
Mucous Membrane
Inflammation
Macrophage Colony-Stimulating Factor
Enterobacteriaceae
Granulocyte-Macrophage Colony-Stimulating Factor
Bone Marrow Cells
Anti-Inflammatory Agents
Hot Temperature

ASJC Scopus subject areas

  • Immunology

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Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. / Kamada, Nobuhiko; Hisamatsu, Tadakazu; Okamoto, Susumu; Sato, Toshiro; Matsuoka, Katsuyoshi; Arai, Kumiko; Nakai, Takaaki; Hasegawa, Akira; Inoue, Nagamu; Watanabe, Noriaki; Akagawa, Kiyoko S.; Hibi, Toshifumi.

In: Journal of Immunology, Vol. 175, No. 10, 15.11.2005, p. 6900-6908.

Research output: Contribution to journalArticle

Kamada, N, Hisamatsu, T, Okamoto, S, Sato, T, Matsuoka, K, Arai, K, Nakai, T, Hasegawa, A, Inoue, N, Watanabe, N, Akagawa, KS & Hibi, T 2005, 'Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria', Journal of Immunology, vol. 175, no. 10, pp. 6900-6908.
Kamada, Nobuhiko ; Hisamatsu, Tadakazu ; Okamoto, Susumu ; Sato, Toshiro ; Matsuoka, Katsuyoshi ; Arai, Kumiko ; Nakai, Takaaki ; Hasegawa, Akira ; Inoue, Nagamu ; Watanabe, Noriaki ; Akagawa, Kiyoko S. ; Hibi, Toshifumi. / Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. In: Journal of Immunology. 2005 ; Vol. 175, No. 10. pp. 6900-6908.
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abstract = "Disorders in enteric bacteria recognition by intestinal macrophages (Mφ) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of Mφ in intestinal inflammation by using an IL-10-deficient (IL-10-/-) mouse colitis model. GM-CSF-induced bone marrow-derived Mφ (GM-Mφ) and M-CSF-induced bone marrow-derived Mφ (M-Mφ) were generated from bone marrow CD11b+ cells. M-Mφ from IL-10-/- mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-Mφ from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-Mφ was not significantly different between WT and IL-10-/- mice. In ex vivo experiments, cytokine production ability of colonic lamina propria Mφ (CLPMφ) but not splenic Mφ from WT mice was similar to that of M-Mφ, and CLPMφ but not splenic Mφ from IL-10-/- mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from IL-10-/- from IL-10-/- mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPMφ and M-Mφ act as anti-inflammatory Mφ and suppress excess inflammation induced by bacteria in WT mice. In IL-10 -/- mice, however, such Mφ subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal Mφ may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal Mφ to gut flora relationship in the development of colitis in IL-10-/- mice.",
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AU - Sato, Toshiro

AU - Matsuoka, Katsuyoshi

AU - Arai, Kumiko

AU - Nakai, Takaaki

AU - Hasegawa, Akira

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AU - Watanabe, Noriaki

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