title: Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway.
abstract: Dendritic cells (DCs) are known as antigen-presenting cells and play a central role in both innate and acquired immunity. Peripheral blood monocytes give rise to resident and recruited DCs in lymph nodes and non-lymphoid tissues. The ligands of nuclear hormone receptors can modulate DC differentiation and so influence various biological functions of DCs. The role of bile acids (BAs) as signalling molecules has recently become apparent, but the functional role of BAs in DC differentiation has not yet been elucidated. We show that DCs derived from human peripheral blood monocytes cultured with a BA produce lower levels of interleukin-12 (IL-12) and tumour necrosis factor-α in response to stimulation with commensal bacterial antigens. Stimulation through the nuclear receptor farnesoid X (FXR) did not affect the differentiation of DCs. However, DCs differentiated with the specific agonist for TGR5, a transmembrane BA receptor, showed an IL-12 hypo-producing phenotype. Expression of TGR5 could only be identified in monocytes and was rapidly down-regulated during monocyte differentiation to DCs. Stimulation with 8-bromoadenosine-cyclic AMP (8-Br-cAMP), which acts downstream of TGR5 signalling, also promoted differentiation into IL-12 hypo-producing DCs. These results indicate that BAs induce the differentiation of IL-12 hypo-producing DCs from monocytes via the TGR5-cAMP pathway.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Riko
authors.initials: R
authors.lastname: Ichikawa
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Takayama
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoneno
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Mina T
authors.initials: MT
authors.lastname: Kitazume
authors.forename: Hajime
authors.initials: H
authors.lastname: Higuchi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D001647:Bile Acids and Salts; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015124:8-Bromo Cyclic Adenosine Monophosphate