Parthenolide, bioactive compound of Chrysanthemum parthenium L., ameliorates fibrogenesis and inflammation in hepatic fibrosis via regulating the crosstalk of TLR4 and STAT3 signaling pathway
Parthenolide, bioactive compound of Chrysanthemum parthenium L., ameliorates fibrogenesis and inflammation in hepatic fibrosis via regulating the crosstalk of TLR4 and STAT3 signaling pathway
复制标题
小白菊内酯是菊花的生物活性化合物，通过调节 TLR4 和 STAT3 信号通路的串扰改善肝纤维化中的纤维形成和炎症
DOI：
10.1002/ptr.7214
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发表时间：
2021-07-12
影响因子：
7.2
通讯作者：
Wu, Yan-Ling
中科院分区：
文献类型：
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作者：
Cui, Zhen-Yu;Wang, Ge;Wu, Yan-Ling
本研究主要研究银胶菊的生物活性成分银胶菊素（PNL）的调控作用，通过调节活化的肝星状细胞（HSC）中Toll样受体4（TLR 4）与信号转导子和转录激活子3（STAT 3）的相互作用，从而达到抗肝纤维化的目的。HSC或Raw 264.7巨噬细胞分别通过TGF-β或LPS活化1小时，然后用PNL、CLI-095（TLR 4抑制剂）或氯硝柳胺（STAT 3抑制剂）处理指定的时间以检测TLR 4和STAT 3的串扰。PNL可显著降低TGF-β激活的HSC中α-SMA、I型胶原的表达及TIMP 1/MMP 13的比值。PNL显著减少促炎细胞因子（包括IL-6、IL-1 β、IL-1 α、IL-18）的释放，并调节信号传导P2 X7 r/NLRP 3轴活化。PNL通过调节bcl-2和caspase家族的表达，明显诱导活化的HSC凋亡。PNL显著抑制TLR 4和STAT 3的表达，包括其下游信号传导。PNL可调节TLR 4和STAT 3的相互作用，这在活化的HSC或Raw 264.7细胞巨噬细胞中被其抑制剂证实。因此，PNL可降低纤维化标志物的表达，减少炎性细胞因子的释放，并诱导活化的HSC凋亡。结论：PNL可双向抑制TLR 4和STAT 3信号通路，阻断TLR 4和STAT 3的相互作用可能是PNL抗肝纤维化的潜在机制。
The current study focused on the regulatory effects of parthenolide (PNL), a bioactive component derived from Chrysanthemum parthenium L., against hepatic fibrosis via regulating the crosstalk of toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) in activated hepatic stellate cells (HSCs). HSCs or Raw 264.7 macrophages were activated by TGF-beta or LPS for 1 hr, respectively, and then treated with PNL, CLI-095 (TLR4 inhibitor), or Niclosamide (STAT3 inhibitor) for the indicated time to detect the crosstalk of TLR4 and STAT3. PNL significantly decreased the expressions of alpha-SMA, collagen I, and the ratio of TIMP1 and MMP13 in TGF-beta-activated HSCs. PNL significantly reduced the releases of pro-inflammatory cytokines, including IL-6, IL-1 beta, IL-1 alpha, IL-18, and regulated signaling P2X7r/NLRP3 axis activation. PNL obviously induced the apoptosis of activated HSCs by regulating bcl-2 and caspases family. PNL significantly inhibited the expressions of TLR4 and STAT3, including their downstream signaling. PNL could regulate the crosstalk of TLR4 and STAT3, which were verified by their inhibitors in activated HSCs or Raw 264.7 cell macrophages. Thus, PNL could decrease the expressions of fibrosis markers, reduce the releases of inflammatory cytokines, and also induce the apoptosis of activated HSCs. In conclusion, PNL could bi-directionally inhibit TLR4 and STAT3 signaling pathway, suggesting that blocking the crosstalk of TLR4 and STAT3 might be the potential mechanism of PNL against hepatic fibrosis.