The G-Protein-Coupled Bile Acid Receptor Gpbar1 (TGR5) Inhibits Gastric Inflammation Through Antagonizing NF-κB Signaling Pathway.
The G-Protein-Coupled Bile Acid Receptor Gpbar1 (TGR5) Inhibits Gastric Inflammation Through Antagonizing NF-κB Signaling Pathway.
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G 蛋白偶联胆汁酸受体 Gpbar1 (TGR5) 通过拮抗 NF-kappa B 信号通路抑制胃炎症
DOI：
10.3389/fphar.2015.00287
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发表时间：
2015
影响因子：
5.6
通讯作者：
Wang YD
中科院分区：
文献类型：
--
作者：
Guo C;Qi H;Yu Y;Zhang Q;Su J;Yu D;Huang W;Chen WD;Wang YD
Gpbar1 (TGR5) 是一种膜结合胆汁酸受体，以其在能量稳态和葡萄糖代谢调节中的作用而闻名。在这里，我们发现缺乏 TGR5 的小鼠比野生型 (WT) 小鼠更容易受到脂多糖 (LPS) 诱导的急性胃炎症的影响，并且 TGR5 通过拮抗 NF-κB 信号通路而成为胃炎症的负调节因子。我们发现 TGR5 配体 23(S)-mCDCA 和 GPBARA（3-(2-氯苯基）-N-(4-氯苯基）-N,5-二甲基异恶唑-4-甲酰胺）的治疗抑制了 NF-κB 信号传导介导的基因和蛋白质表达。 TGR5 过表达配体处理抑制了 LPS 诱导的干扰素诱导蛋白 10 (IP-10)、TNF-α 和趋化蛋白 1 (MCP-1) 的基因表达。此外，我们发现TGR5激活通过抑制其转录活性、IκBα磷酸化和p65易位来拮抗NF-κB信号通路，这表明TGR5至少部分通过抑制NF-κB信号传导来拮抗胃部炎症。这些发现确定 TGR5 是胃炎症的负介质，可能作为人类胃炎症和癌症的有吸引力的治疗工具。
Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well-known for its roles in regulation of energy homeostasis and glucose metabolism. Here, we show that mice lacking TGR5 were much more susceptible to lipopolysaccharide (LPS)-induced acute gastric inflammation than wild-type (WT) mice and TGR5 is a negative regulator of gastric inflammation through antagonizing NF-κB signaling pathway. We found that the treatment of TGR5 ligands 23(S)-mCDCA and GPBARA (3-(2-Chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide) suppressed gene and protein expression mediated by NF-κB signaling. TGR5 overexpression with ligand treatment inhibited gene expression of interferon-inducible protein 10 (IP-10), TNF-α, and chemoattractant protein-1 (MCP-1) induced by LPS. Furthermore, we revealed that TGR5 activation antagonized NF-κB signaling pathway through suppressing its transcription activity, the phosphorylation of IκBα and p65 translocation, which suggests that TGR5 antagonizes gastric inflammation at least in part by inhibiting NF-κB signaling. These findings identify TGR5 as a negative mediator of gastric inflammation that may serve as an attractive therapeutic tool for human gastric inflammation and cancer.