Sphingosine 1-phosphate protects primary human keratinocytes from apoptosis via nitric oxide formation through the receptor subtype S1P3
Sphingosine 1-phosphate protects primary human keratinocytes from apoptosis via nitric oxide formation through the receptor subtype S1P3
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DOI：
10.1007/s11010-012-1433-5
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发表时间：
2012-08
影响因子：
4.3
通讯作者：
E. I. Schmitz;Henrik Potteck;Melanie Schüppel;M. Manggau;Elly Wahydin;B. Kleuser
中科院分区：
文献类型：
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作者：
E. I. Schmitz;Henrik Potteck;Melanie Schüppel;M. Manggau;Elly Wahydin;B. Kleuser
虽然脂质介质鞘氨醇1-磷酸（S1 P）已被确定为诱导人角质形成细胞的细胞生长停滞，鞘脂有效地保护这些表皮细胞免于凋亡。S1 P诱导的抗凋亡作用的分子机制的特点是少。除了S1 P，内源性产生的一氧化氮（NO·）已被认为是角质形成细胞凋亡的有效调节剂。因此，阐明S1 P是否通过NO·依赖的信号通路保护人角质形成细胞具有重要意义。事实上，S1 P诱导人角质形成细胞中内皮型一氧化氮合酶（eNOS）的活化，导致NO·的形成增强。最有趣的是，在eNOS抑制剂L-NAME的存在下以及eNOS缺陷的角质形成细胞中，S1 P的细胞保护作用几乎完全消除，表明鞘脂代谢物S1 P通过eNOS活化和随后产生保护量的NO·来保护人角质形成细胞免于凋亡。众所周知，S1 P的大多数已知作用是由五种特异性G蛋白偶联受体家族介导的。因此，S1 P-受体亚型参与S1 P-介导的eNOS激活已被检查。事实上，这项研究清楚地表明，S1 P3是唯一的受体亚型在人类角质形成细胞介导eNOS激活和NO·的形成响应于S1 P。一致的是，当S1 P3受体亚型被废除时，S1 P几乎完全失去了保护人角质形成细胞免于凋亡的能力。
Although the lipid mediator sphingosine 1-phosphate (S1P) has been identified to induce cell growth arrest of human keratinocytes, the sphingolipid effectively protects these epidermal cells from apoptosis. The molecular mechanism of the anti-apoptotic action induced by S1P is less characterized. Apart from S1P, endogenously produced nitric oxide (NO•) has been recognized as a potent modulator of apoptosis in keratinocytes. Therefore, it was of great interest to elucidate whether S1P protects human keratinocytes via a NO•-dependent signalling pathway. Indeed, S1P induced an activation of endothelial nitric oxide synthase (eNOS) in human keratinocytes leading to an enhanced formation of NO•. Most interestingly, the cell protective effect of S1P was almost completely abolished in the presence of the eNOS inhibitor L-NAME as well as in eNOS-deficient keratinocytes indicating that the sphingolipid metabolite S1P protects human keratinocytes from apoptosis via eNOS activation and subsequent production of protective amounts of NO•. It is well established that most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Therefore, the involvement of S1P-receptor subtypes in S1P-mediated eNOS activation has been examined. Indeed, this study clearly shows that the S1P3is the exclusive receptor subtype in human keratinocytes which mediates eNOS activation and NO•formation in response to S1P. In congruence, when the S1P3receptor subtype is abrogated, S1P almost completely lost its ability to protect human keratinocytes from apoptosis.