Pien Tze Huang (PZH), a class I nationally protected traditional Chinese medicine (TCM), has been used to treat liver diseases such as hepatitis; however, the effect of PZH on the progression of sepsis is unknown. Here, we reported that PZH attenuated lipopolysaccharide (LPS)-induced sepsis in mice and reduced LPS-induced production of proinflammatory cytokines in macrophages by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalling. Mechanistically, PZH stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation to induce the expression of A20, which could inhibit the activation of NF-κB and MAPK signalling. Knockdown of the bile acid (BA) receptor G protein-coupled bile acid receptor 1 (TGR5) in macrophages abolished the effects of PZH on STAT3 phosphorylation and A20 induction, as well as the LPS-induced inflammatory response, suggesting that BAs in PZH may mediate its anti-inflammatory effects by activating TGR5. Consistently, deprivation of BAs in PZH by cholestyramine resin reduced the effects of PZH on the expression of phosphorylated-STAT3 and A20, the activation of NF-κB and MAPK signalling, and the production of proinflammatory cytokines, whereas the addition of BAs to cholestyramine resin-treated PZH partially restored the inhibitory effects on the production of proinflammatory cytokines. Overall, our study identifies BAs as the effective components in PZH that activate TGR5-STAT3-A20 signalling to ameliorate LPS-induced sepsis.

中文翻译：

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中药片仔癀通过胆汁酸介导的 TGR5-STAT3-A20 信号激活改善 LPS 诱导的脓毒症

片仔癀（PZH）是国家一级保护中药，用于治疗肝炎等肝脏疾病；然而，PZH 对脓毒症进展的影响尚不清楚。在此，我们报道 PZH 通过抑制丝裂原激活蛋白激酶 (MAPK) 和核因子 kappa B (NF-κB) 的激活，减轻脂多糖 (LPS) 诱导的小鼠脓毒症，并减少 LPS 诱导的巨噬细胞中促炎细胞因子的产生) 信号。从机制上讲，PZH 刺激信号转导子和转录激活子 3 (STAT3) 磷酸化，诱导 A20 的表达，从而抑制 NF-κB 和 MAPK 信号传导的激活。巨噬细胞中胆汁酸 (BA) 受体 G 蛋白偶联胆汁酸受体 1 (TGR5) 的敲低消除了 PZH 对 STAT3 磷酸化和 A20 诱导以及 LPS 诱导的炎症反应的影响，表明 PZH 中的 BA 可能通过激活 TGR5 介导其抗炎作用。一致地，考来烯胺树脂剥夺 PZH 中的 BA 会降低 PZH 对磷酸化 STAT3 和 A20 表达、NF-κB 和 MAPK 信号传导以及促炎细胞因子产生的影响，而向考来烯胺树脂中添加 BA -治疗的PZH部分恢复了对促炎细胞因子产生的抑制作用。总体而言，我们的研究确定 BA 是 PZH 中的有效成分，可激活 TGR5-STAT3-A20 信号传导以改善 LPS 诱导的脓毒症。