TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

Kazuaki Yoneno, Tadakazu Hisamatsu, Katsuyoshi Shimamura, Nobuhiko Kamada, Riko Ichikawa, Mina T. Kitazume, Maiko Mori, Michihide Uo, Yuka Namikawa, Katsuyoshi Matsuoka, Toshiro Sato, Kazutaka Koganei, Akira Sugita, Takanori Kanai, Toshifumi Hibi

研究成果: Article

65 引用 (Scopus)

抄録

Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mφ{symbol}s) and dendritic cells. Mφ{symbol}s differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mφ{symbol}s), which are similar to the human intestinal lamina propria CD14+ Mφ{symbol}s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mφ{symbol} and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mφ{symbol}s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mφ{symbol}s from patients with CD expressed TGR5. In isolated intestinal CD14+ Mφ{symbol}s, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.

元の言語English
ページ(範囲)19-29
ページ数11
ジャーナルImmunology
139
発行部数1
DOI
出版物ステータスPublished - 2013 5

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Bile Acids and Salts
Crohn Disease
Mucous Membrane
Macrophages
Cytokines
Dendritic Cells
Tumor Necrosis Factor-alpha
Lithocholic Acid
Bacterial Antigens
Macrophage Colony-Stimulating Factor
Deoxycholic Acid
Cell Lineage
Intestinal Mucosa
Inflammatory Bowel Diseases
Lipid Metabolism
Interferons
Lipopolysaccharides
Monocytes
Signal Transduction
Phosphorylation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

これを引用

TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. / Yoneno, Kazuaki; Hisamatsu, Tadakazu; Shimamura, Katsuyoshi; Kamada, Nobuhiko; Ichikawa, Riko; Kitazume, Mina T.; Mori, Maiko; Uo, Michihide; Namikawa, Yuka; Matsuoka, Katsuyoshi; Sato, Toshiro; Koganei, Kazutaka; Sugita, Akira; Kanai, Takanori; Hibi, Toshifumi.

:: Immunology, 巻 139, 番号 1, 05.2013, p. 19-29.

研究成果: Article

Yoneno, K, Hisamatsu, T, Shimamura, K, Kamada, N, Ichikawa, R, Kitazume, MT, Mori, M, Uo, M, Namikawa, Y, Matsuoka, K, Sato, T, Koganei, K, Sugita, A, Kanai, T & Hibi, T 2013, 'TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease', Immunology, 巻. 139, 番号 1, pp. 19-29. https://doi.org/10.1111/imm.12045
Yoneno, Kazuaki ; Hisamatsu, Tadakazu ; Shimamura, Katsuyoshi ; Kamada, Nobuhiko ; Ichikawa, Riko ; Kitazume, Mina T. ; Mori, Maiko ; Uo, Michihide ; Namikawa, Yuka ; Matsuoka, Katsuyoshi ; Sato, Toshiro ; Koganei, Kazutaka ; Sugita, Akira ; Kanai, Takanori ; Hibi, Toshifumi. / TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. :: Immunology. 2013 ; 巻 139, 番号 1. pp. 19-29.
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abstract = "Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mφ{symbol}s) and dendritic cells. Mφ{symbol}s differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mφ{symbol}s), which are similar to the human intestinal lamina propria CD14+ Mφ{symbol}s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mφ{symbol} and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mφ{symbol}s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mφ{symbol}s from patients with CD expressed TGR5. In isolated intestinal CD14+ Mφ{symbol}s, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.",
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AU - Yoneno, Kazuaki

AU - Hisamatsu, Tadakazu

AU - Shimamura, Katsuyoshi

AU - Kamada, Nobuhiko

AU - Ichikawa, Riko

AU - Kitazume, Mina T.

AU - Mori, Maiko

AU - Uo, Michihide

AU - Namikawa, Yuka

AU - Matsuoka, Katsuyoshi

AU - Sato, Toshiro

AU - Koganei, Kazutaka

AU - Sugita, Akira

AU - Kanai, Takanori

AU - Hibi, Toshifumi

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N2 - Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mφ{symbol}s) and dendritic cells. Mφ{symbol}s differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mφ{symbol}s), which are similar to the human intestinal lamina propria CD14+ Mφ{symbol}s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mφ{symbol} and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mφ{symbol}s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mφ{symbol}s from patients with CD expressed TGR5. In isolated intestinal CD14+ Mφ{symbol}s, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.

AB - Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mφ{symbol}s) and dendritic cells. Mφ{symbol}s differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mφ{symbol}s), which are similar to the human intestinal lamina propria CD14+ Mφ{symbol}s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mφ{symbol} and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mφ{symbol}s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mφ{symbol}s from patients with CD expressed TGR5. In isolated intestinal CD14+ Mφ{symbol}s, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.

KW - Bile acid

KW - Crohn's disease

KW - Intestinal macrophage

KW - TGR5

KW - Tumour necrosis factor α

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