Urocortin participates in LPS-induced apoptosis of THP-1 macrophages via S1P-cPLA2 signaling pathway
Urocortin participates in LPS-induced apoptosis of THP-1 macrophages via S1P-cPLA2 signaling pathway
复制标题
Urocortin 通过 S1P-cPLA2 信号通路参与 LPS 诱导的 THP-1 巨噬细胞凋亡。
DOI：
10.1016/j.ejphar.2020.173559
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发表时间：
2020-11-15
影响因子：
5
通讯作者：
Li，Shengnan
中科院分区：
文献类型：
--
作者：
Zhu，Chao;Zhou，Jun;Li，Shengnan
尿皮质素（UCN）对巨噬细胞凋亡的影响目前还未见报道。潜在的机制也不清楚。本研究旨在探讨UCN是否参与调节LPS诱导的巨噬细胞凋亡，从而通过靶向PLA 2预防动脉粥样硬化病变的发展。流式细胞仪分析显示，LPS处理后，人THP-1巨噬细胞的细胞凋亡增加了50%以上。LPS诱导的巨噬细胞凋亡与Lp-PLA 2和cPLA 2有关，NF-κB对Lp-PLA 2和cPLA 2表达的影响存在差异。然而，NF-κB对Lp-PLA 2和cPLA 2表达的反向调节表明NF-κB可能不是调节巨噬细胞凋亡的关键靶点。有趣的是，我们发现cPLA 2的大约三倍上调与LPS诱导的S1 P形成和细胞凋亡一致。LPS使UCN的表达明显降低约50%，分泌减少约25%。酶抑制剂和cPLA 2基因敲低表达均能完全阻断LPS诱导的细胞凋亡。此外，Sphk 1抑制剂PF-543抑制S1 P的合成减少了cPLA 2的表达和细胞凋亡，但同时恢复了细胞培养上清液中UCN的正常水平。此外，加入外源性UCN也逆转LPS诱导的cPLA 2表达和细胞凋亡。UCN可能是LPS-S1 P-cPLA 2-凋亡通路的反向调节剂，从而有助于防止不稳定斑块的形成。
There is little literature showing the effect of urocortin (UCN) on macrophage apoptosis. The underlying mechanism is also unclear. This work was to investigate the involvement of UCN in the regulation of LPS-induced macrophage apoptosis and hence in the prevention from the atherosclerotic lesion development through targeting PLA2. Flow cytometry analysis showed that cell apoptosis was increased by more than 50% after LPS treatment in human THP-1 macrophage. Lp-PLA2 and cPLA2 were found to mediate LPS-induced macrophage apoptosis and NF-κB differentially influenced the expression of Lp-PLA2 and cPLA2. However, the reverse regulation of the expression of Lp-PLA2 and cPLA2 by NF-κB suggested that NF-κB may not be a key target for regulating macrophage apoptosis. Interestingly, we found that the approximate three folds upregulation of cPLA2 was in line with the induction of S1P formation and cell apoptosis by LPS. Inversely, LPS obviously decreased UCN expression by about 50% and secretion by about 25%. Both the enzyme inhibitor and knockdown expression of cPLA2 could completely abolish LPS-induced cell apoptosis. In addition, suppression of S1P synthesis by Sphk1 inhibitor PF-543 reduced the expression of cPLA2 and cell apoptosis but at the same time restored the normal level of UCN in cell culture supernatant. Furthermore, addition of exogenous UCN also reversed LPS-induced expression of cPLA2 and apoptosis. Taken together, UCN may be the reverse regulator of LPS-S1P-cPLA2-apoptosis pathway, thereby contributing to the prevention from the formation of unstable plaques.