Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis
Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis
复制标题
芳烃受体的激活使人角质形成细胞对 CD95L 和 TRAIL 诱导的细胞凋亡敏感
作者：
Kristin Stolpmann;J. Brinkmann;S. Salzmann;D. Genkinger;E. Fritsche;C. Hutzler;Harald Wajant;A. Luch;F. Henkler
在这项研究中，我们分析了普遍存在的环境毒素苯并[a]芘（BP）在HaCaT细胞和人角质形成细胞的凋亡作用。虽然长时间暴露于BP本身没有细胞毒性，但在激活芳烃受体（AhR）的浓度下，观察到BP强烈增强CD 95（Fas）介导的细胞凋亡。重要的是，最终致突变的BP代谢物，即（+）-抗BP-7，8-二醇-9，10-环氧化物（BPDE），未能增强CD 95介导的细胞死亡，表明观察到的BP促凋亡作用与DNA加合物或DNA损伤相关的信号传导无关。CD 95诱导的细胞凋亡也被β-萘黄酮增强，β-萘黄酮是一种众所周知的不诱导DNA损伤的AhR激动剂，因此表明AhR活化的关键作用。因此，BP不能敏化CD 95 L诱导的AhR敲低HaCaT细胞凋亡。此外，抑制CYP 1A 1和/或1B 1表达不影响促凋亡串扰。暴露于BP没有增加CD 95的表达，但导致caspase-8的活化增强。还观察到通过与CD 95类似的机制激活半胱天冬酶-8和凋亡的TRAIL死亡受体的凋亡增强。总之，这些观察结果表明AhR信号传导与CD 95和TRAIL受体共享的受体相关信号传导中间体的活性的干扰。因此，我们的数据表明，AhR激动剂可以增强皮肤暴露后的苦参碱介导的逆境。
In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[a]pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by β-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure.
影响因子：
3.6
作者：
Levine-Fridman, A;Chen, L;Elferink, CJ
通讯作者：
Elferink, CJ
苯并[a]芘醌诱导的对 DBA/2 小鼠原代培养骨髓基质细胞毒性的表征：线粒体功能障碍的潜在作用。
影响因子：
3.8
作者：
Zhu,H;Li,Y;Trush,MA
通讯作者：
Trush,MA