College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010018, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Hohhot 010018, China.
College of Forestry, Inner Mongolia Agricultural University, Hohhot 010018, China.
Chin J Nat Med. 2020 Dec;18(12):898-906. doi: 10.1016/S1875-5364(20)60033-4.
Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.
牛磺胆酸（TCDCA）是胆酸的主要有效成分之一，通过 TGR5 受体在细胞凋亡和免疫反应中发挥关键作用。在这项研究中，我们揭示了 TCDCA 与 TGR5 受体在 TGR5 敲低 H1299 细胞中的相互作用，以及 TGR5 受体在 NR8383 巨噬细胞中通过环磷酸腺苷（cAMP）-蛋白激酶 A（PKA）-cAMP 反应元件结合（CREB）信号通路对炎症的调节作用。在 TGR5 敲低 H1299 细胞中，TCDCA 通过 TGR5 受体显著激活 cAMP 水平，表明 TCDCA 可以与 TGR5 结合；在 NR8383 巨噬细胞中，与使用腺苷酸环化酶（AC）抑制剂 SQ22536 相比，TCDCA 增加了 cAMP 含量。此外，与抑制剂组相比，激活的 cAMP 可以显著增强其下游蛋白 PKA 和 CREB 的基因表达和蛋白水平。此外，TCDCA 通过激活 B 细胞核因子 κ 轻链增强子（NF-κB）活性降低肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、IL-6、IL-8 和 IL-12。PKA 和 CREB 是抗炎和免疫反应的主要调节因子。因此，我们的研究结果表明，TCDCA 通过 TGR5 受体诱导的 cAMP-PKA-CREB 信号通路发挥重要的抗炎作用。
