Peus D, Meves A, Pott M, Beyerle A, Pittelkow M R
Departments of Dermatology and Biochemistry and Molecular Biology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Free Radic Biol Med. 2001 Feb 15;30(4):425-32. doi: 10.1016/s0891-5849(00)00488-3.
We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H(2)O(2) generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure-increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.
我们最近发现，将人角质形成细胞暴露于生理剂量的紫外线B（UVB）下，会通过活性氧激活表皮生长因子受体（EGFR）/细胞外调节激酶1和2（ERK1/2）以及p38信号通路，抗氧化剂可调节这一效应。生育三烯酚（Trolox）是一种水溶性维生素E类似物，是目前正在研究的具有预防和保护潜力、可抵御紫外线辐射对皮肤有害影响的抗氧化剂之一。我们发现，生育三烯酚以浓度依赖的方式抑制原代角质形成细胞中基础状态和UVB诱导的细胞内过氧化氢生成。生育三烯酚对UVB诱导的EGFR磷酸化没有显著影响。在暴露于UVB之前向细胞中添加较低浓度的生育三烯酚时，观察到对ERK1/2激活的抑制作用更强，而添加较高浓度的生育三烯酚时，对p38激活的抑制作用更强。同样，在UVB暴露前用生育三烯酚进行预处理的时长方面也发现了不同的影响——预处理间隔较短时，对ERK1/2激活的抑制作用增强，预处理间隔较长时，对p38激活的抑制作用增强。生育三烯酚可有效抑制UVB诱导的c-jun氨基末端激酶激活。此外，延长生育三烯酚的预处理时间可降低UVB照射后细胞的死亡率。总之，生育三烯酚对UVB诱导的信号通路激活具有不同的调节作用。对生育三烯酚及其代谢产物的时间依赖性生物激活以及信号转导与细胞结果的调节进行进一步研究，应有助于制定合理的药物应用策略。
