title: TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease.
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 (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mϕs), which are similar to the human intestinal lamina propria CD14(+) Mϕs 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 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-Mϕs 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 Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14(+) Mϕs, 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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoneno
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Shimamura
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Riko
authors.initials: R
authors.lastname: Ichikawa
authors.forename: Mina T
authors.initials: MT
authors.lastname: Kitazume
authors.forename: Maiko
authors.initials: M
authors.lastname: Mori
authors.forename: Michihide
authors.initials: M
authors.lastname: Uo
authors.forename: Yuka
authors.initials: Y
authors.lastname: Namikawa
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Koganei
authors.forename: Akira
authors.initials: A
authors.lastname: Sugita
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003840:Deoxycholic Acid / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008095:Lithocholic Acid / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000276:immunology / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D002756:Cholagogues and Choleretics; D016207:Cytokines; D003902:Detergents; C473772:GPBAR1 protein, human; C573415:IFNG protein, human; D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; C498143:RELA protein, human; D043562:Receptors, G-Protein-Coupled; D051996:Transcription Factor RelA; D003840:Deoxycholic Acid; D008095:Lithocholic Acid; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma