Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts
Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts
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DOI：
10.1074/jbc.m202798200
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发表时间：
2002-10-04
影响因子：
4.8
通讯作者：
Lotersztajn, S
中科院分区：
文献类型：
--
作者：
Davaille, J;Li, LY;Lotersztajn, S
肝肌成纤维细胞（hMF）是慢性肝病期间肝纤维化发展的核心，通过细胞凋亡清除它们有助于肝纤维化的解决。我们之前在人类 hMF 中鉴定了 1-磷酸鞘氨醇 (S1P) 的 Edg 受体。在这里，我们研究了 S1P 对 hMF 凋亡的影响。 S1P 通过凋亡过程降低血清剥夺 hMF 的活力，该过程与 S1P 转化为鞘氨醇和神经酰胺无关。 S1P 的凋亡作用不依赖于受体，因为 Edg 激动剂二氢-S1P 没有作用。在百日咳毒素存在的情况下，S1P 增强了 caspase-3 的激活，揭示了 S1P 还刺激了受体依赖性生存途径。细胞存活依赖于两种百日咳毒素敏感事件，即 S1P 激活 ERK 和激活磷脂酰肌醇 3-激酶 (PI3K)/Akt。这两条途径也被二氢-S1P 激活。减弱 ERK 或 PI3K 会增强 S1P 对 caspase-3 的刺激，同时抑制这两种途径会导致 caspase-3 激活的叠加效应。总之，S1P 通过受体独立机制诱导人类 hMF 凋亡，并在 Edg 受体激活后刺激生存途径。生存途径源自 G(i)/G(o) 蛋白的连续激活以及 ERK 和 PI3K/Akt 的独立刺激。因此，阻断 Edg 受体可能会使肝肌成纤维细胞对 S1P 引起的细胞凋亡敏感。
Hepatic myofibroblasts (hMFs) are central in the development of liver fibrosis during chronic liver diseases, and their removal by apoptosis contributes to the resolution of liver fibrosis. We previously identified Edg receptors for sphingosine 1-phosphate (S1P) in human hMFs. Here, we investigated the effects of S1P on hMF apoptosis. S1P reduced viability of serum-deprived hMFs by an apoptotic process that was unrelated to the conversion of S1P into sphingosine and ceramide. The apoptotic effects of S1P were receptor-independent because dihydro-S1P, an Edg agonist, had no effect. S1P also stimulated a receptor-dependent survival pathway, revealed by enhanced activation of caspase-3 by S1P in the presence of pertussis toxin. Cell survival relied on two pertussis toxin-sensitive events, activation of ERK and activation of phosphatidylinositol 3-kinase (PI3K)/Akt by S1P. Both pathways were also activated by dihydro-S1P. Blunting either ERK or PI3K enhanced caspase-3 stimulation by S1P, and simultaneous inhibition of both pathways resulted in additive effects on caspase-3 activation. In conclusion, S1P induces apoptosis of human hMFs via a receptor-independent mechanism and stimulates a survival pathway following activation of Edg receptors. The survival pathway arises from the sequential activation of G(i)/G(o) proteins and independent stimulations of ERK and PI3K/Akt. Therefore, blocking Edg receptors may sensitize hepatic myofibroblasts to apoptosis by S1P.