TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease.
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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
TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease.
Immunology. 2013 May;139(1):19-29. doi: 10.1111/imm.12045.
- PubMed ID
- 23566200 [ View in PubMed]
- 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 (Mvarphis) and dendritic cells. Mvarphis differentiated with macrophage colony-stimulating factor and interferon-gamma (Mgamma-Mvarphis), which are similar to the human intestinal lamina propria CD14(+) Mvarphis that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mvarphi 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-alpha production in Mgamma-Mvarphis 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-kappaB 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 Mvarphis from patients with CD expressed TGR5. In isolated intestinal CD14(+) Mvarphis, a TGR5 agonist could inhibit tumour necrosis factor-alpha production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Deoxycholic acid G-protein coupled bile acid receptor 1 Protein Humans UnknownNot Available Details