Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway
Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway
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DOI：
10.1111/j.1365-2567.2012.03554.x
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发表时间：
2012-06-01
期刊：
影响因子：
6.4
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
--
作者：
Ichikawa, Riko;Takayama, Tetsuro;Hibi, Toshifumi
树突状细胞（Dendritic cells，DC）是一种抗原提呈细胞，在先天性免疫和获得性免疫中发挥重要作用。外周血单核细胞在淋巴结和非淋巴组织中产生驻留和募集的DC。核激素受体的配体可以调节DC的分化，从而影响DC的多种生物学功能。胆汁酸（BA）作为信号分子的作用最近变得明显，但BA在DC分化中的功能作用尚未阐明。我们发现，来自人外周血单核细胞培养的树突状细胞与BA产生较低水平的白细胞介素-12（IL-12）和肿瘤坏死因子-a的刺激与大肠杆菌抗原。通过核受体法尼醇X（FXR）的刺激不影响DC的分化。然而，DC分化与TGR 5，跨膜BA受体的特异性激动剂，表现出IL-12低生产表型。TGR 5的表达仅在单核细胞中被鉴定，并且在单核细胞分化为DC期间迅速下调。用作用于TGR 5信号传导下游的8-溴腺苷环磷酸（8-Br-cAMP）刺激也促进分化为IL-12低产生DC。这些结果表明，BA通过TGR 5-cAMP途径诱导单核细胞分化为IL-12低产生DC。
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-a 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.