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TGR 5 signalling inhibits the production of pro‐inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease
Author(s) -
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
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12045
Subject(s) - g protein coupled bile acid receptor , biology , deoxycholic acid , cd14 , tumor necrosis factor alpha , proinflammatory cytokine , signal transduction , immunology , microbiology and biotechnology , inflammation , receptor , immune system , bile acid , biochemistry
Summary Bile acids ( BA s) play important roles not only in lipid metabolism, but also in signal transduction. TGR 5, a transmembrane receptor of BA s, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BA s operate in immunological responses via the TGR 5 pathway in human mononuclear cell lineages. We examined TGR 5 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 CD 14 + Mϕs that contribute to Crohn's disease ( CD ) pathogenesis by production of pro‐inflammatory cytokines, highly expressed TGR 5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR 5 agonist and two types of BA s, 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 TGR 5– cAMP pathway to induce phosphorylation of c‐ F os that regulated nuclear factor‐κ B p65 activation. Next, we analysed TGR 5 levels in lamina propria mononuclear cells ( LPMC s) obtained from the intestinal mucosa of patients with CD . Compared with non‐inflammatory bowel disease, inflamed CD LPMC s contained more TGR 5 transcripts. Among LPMC s, isolated CD 14 + intestinal Mϕs from patients with CD expressed TGR 5. In isolated intestinal CD 14 + Mϕs, a TGR 5 agonist could inhibit tumour necrosis factor‐α production. These results indicate that TGR 5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.