School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
J Invest Dermatol. 2010 Apr;130(4):1095-106. doi: 10.1038/jid.2009.436. Epub 2010 Jan 21.
The role of reactive oxygen species (ROS) in UVB-induced apoptosis has been established, but the molecular mechanisms of their production in response to UVB irradiation in keratinocytes are not well understood. In this study, we demonstrate that levels of BLT2, a low-affinity leukotriene B(4) receptor, and its ligands (LTB(4) and 12(S)-HETE) are greatly increased by UVB irradiation and are responsible for the UVB-induced ROS generation in human keratinocytes. Blockade of BLT2 with a BLT2-specific antagonist, LY255283, or with siBLT2 attenuated ROS production and apoptotic cell death detected by a number of criteria. Moreover, we found that the NADPH oxidase family protein Nox1 lies downstream of BLT2 and mediates UVB-induced ROS production and apoptosis. Topical treatment of mouse epidermal skin with LY255283 gave significant protection against UVB-induced sunburn-associated apoptotic damage. Finally, when BLT2-overexpressing transgenic mice were irradiated with UVB, we observed more extensive skin apoptosis. Taken together, our results demonstrate that a "BLT2-Nox1"-linked pathway has a crucial role in UVB-induced ROS generation and mediates apoptosis in human keratinocytes.
活性氧（ROS）在 UVB 诱导的细胞凋亡中的作用已得到确立，但角化细胞对 UVB 照射产生 ROS 的分子机制尚不清楚。在本研究中，我们证明 BLT2（一种低亲和力白三烯 B4 受体）及其配体（LTB4 和 12(S)-HETE）的水平在 UVB 照射下大大增加，并且负责人类角化细胞中 UVB 诱导的 ROS 生成。BLT2 特异性拮抗剂 LY255283 或 siBLT2 阻断 BLT2 可减弱 ROS 生成和通过多种标准检测到的凋亡细胞死亡。此外，我们发现 NADPH 氧化酶家族蛋白 Nox1 位于 BLT2 下游，介导 UVB 诱导的 ROS 生成和凋亡。用 LY255283 对小鼠表皮皮肤进行局部治疗可显著防止 UVB 诱导的晒伤相关凋亡损伤。最后，当 BLT2 过表达转基因小鼠被 UVB 照射时，我们观察到更广泛的皮肤凋亡。总之，我们的结果表明，“BLT2-Nox1”相关途径在 UVB 诱导的 ROS 生成中起关键作用，并介导人类角质形成细胞的凋亡。
