Kim Dong-Seok, Kim Sook-Young, Lee Jai-Eun, Kwon Sun-Bang, Joo Young-Hyun, Youn Sang-Woong, Park Kyoung-Chan
Research Division for Human Life Sciences, Seoul National University, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea.
Arch Pharm Res. 2003 Sep;26(9):739-46. doi: 10.1007/BF02976685.
Ultraviolet B (UVB) is known to induce apoptosis in human melanocytes. Here we show the cytoprotective effect of sphingosine-1-phosphate (S1P) against UVB-induced apoptosis. We also show that UVB-induced apoptosis of melanocytes is mediated by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage, and that S1P prevents apoptosis by inhibiting this apoptotic pathway. We further investigated three major mitogen-activated protein (MAP) kinases after UVB irradiation. UVB gradually activated c-Jun N-terminal kinase (JNK) and p38 MAP kinase, while extracellular signal-regulated protein kinase (ERK) was inactivated transiently. Blocking of the p38 MAP kinase pathway using SB203580 promoted cell survival and inhibited the activation of caspase-3 and PARP cleavage. These results suggest that p38 MAP kinase activation may play an important role in the UVB-induced apoptosis of human melanocytes. To explain this cytoprotective effect, we next examined whether S1P could inhibit UVB-induced JNK and p38 MAP kinase activation. However, S1P was not found to have any influence on UVB-induced JNK or p38 MAP kinase activation. In contrast, S1P clearly stimulated the phosphorylation of ERK, and the specific inhibition of the ERK pathway using PD98059 abolished the cytoprotective effect of S1P. Based on these results, we conclude that the activation of p38 MAP kinase plays an important role in UVB-induced apoptosis, and that S1P may show its cytoprotective effect through ERK activation in human melanocytes.
已知紫外线B（UVB）可诱导人黑素细胞凋亡。在此我们展示了鞘氨醇-1-磷酸（S1P）对UVB诱导凋亡的细胞保护作用。我们还表明，UVB诱导的黑素细胞凋亡是由半胱天冬酶-3激活和聚（ADP-核糖）聚合酶（PARP）裂解介导的，并且S1P通过抑制该凋亡途径来预防凋亡。我们进一步研究了UVB照射后三种主要的丝裂原活化蛋白（MAP）激酶。UVB逐渐激活c-Jun氨基末端激酶（JNK）和p38 MAP激酶，而细胞外信号调节蛋白激酶（ERK）则短暂失活。使用SB203580阻断p38 MAP激酶途径可促进细胞存活并抑制半胱天冬酶-3的激活和PARP裂解。这些结果表明，p38 MAP激酶激活可能在UVB诱导的人黑素细胞凋亡中起重要作用。为了解释这种细胞保护作用，我们接下来检查了S1P是否可以抑制UVB诱导的JNK和p38 MAP激酶激活。然而，未发现S1P对UVB诱导的JNK或p38 MAP激酶激活有任何影响。相反，S1P明显刺激了ERK的磷酸化，并且使用PD98059特异性抑制ERK途径消除了S1P的细胞保护作用。基于这些结果，我们得出结论，p38 MAP激酶的激活在UVB诱导的凋亡中起重要作用，并且S1P可能通过人黑素细胞中的ERK激活来显示其细胞保护作用。
