Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, PR China.
Respir Physiol Neurobiol. 2011 Aug 15;177(3):241-6. doi: 10.1016/j.resp.2011.04.016. Epub 2011 Apr 22.
Recent evidence suggests that TGF-β1 has a dual role in regulating cell response to Fas/Fas ligand (FasL)-induced apoptosis. TGF-β1 may play a positive or negative role on cell sensitivity to apoptosis via Fas/FasL system, depending on cell types and their specific environment. TGF-β1 and the Fas/FasL system are also involved in pathological processes of acute lung injury (ALI) and interstitial lung diseases including early lung injury and subsequent tissue repair. However, it is not well understood how TGF-β1 regulates Fas/FasL mediated apoptotic signaling in lung epithelium. In this study, we found that TGF-β1 could affect the sensitivity of lung epithelial A549 cells to Fas/FasL mediated apoptosis in a time-dependent manner. Apoptosis of A549 cells could be enhanced significantly by co-treatment with TGF-β1 and FasL, or pretreatment with TGF-β1 followed by FasL exposure, as evidenced by markedly increased caspase-8 and JNK activities. However, prolonged exposure to TGF-β1 could result in an obvious inhibition of the Fas/FasL-induced apoptosis, accompanied by down-regulation of Fas and up-regulation of c-Flip. Our results also showed that the effect of TGF-β1 on cell sensitivity to Fas-mediated apoptosis was independent of Akt pathway activation. These findings suggest that timely interplay of TGF-β1 and the Fas/FasL system could determine the final outcomes of cell survival/death signaling, for example, switching cell death signaling to survival signaling during early injury and later repair process of lung epithelium.
最近的证据表明，TGF-β1 在调节细胞对 Fas/Fas 配体（FasL）诱导的细胞凋亡的反应中具有双重作用。TGF-β1 可能通过 Fas/FasL 系统对细胞对细胞凋亡的敏感性发挥正或负作用，具体取决于细胞类型及其特定的环境。TGF-β1 和 Fas/FasL 系统还参与急性肺损伤（ALI）和间质性肺疾病的病理过程，包括早期肺损伤和随后的组织修复。然而，TGF-β1 如何调节肺上皮细胞中 Fas/FasL 介导的凋亡信号通路尚不清楚。在本研究中，我们发现 TGF-β1 可以时间依赖的方式影响肺上皮细胞 A549 对 Fas/FasL 介导的细胞凋亡的敏感性。TGF-β1 和 FasL 共同处理或 TGF-β1 预处理后 FasL 暴露均可显著增强 A549 细胞的凋亡，这表现在 caspase-8 和 JNK 活性明显增加。然而，长时间暴露于 TGF-β1 可导致 Fas/FasL 诱导的凋亡明显抑制，同时 Fas 下调和 c-Flip 上调。我们的结果还表明，TGF-β1 对 Fas 介导的细胞凋亡敏感性的影响与 Akt 途径的激活无关。这些发现表明，TGF-β1 和 Fas/FasL 系统之间的适时相互作用可以决定细胞存活/死亡信号的最终结果，例如，在肺上皮细胞的早期损伤和后期修复过程中，将细胞死亡信号转换为存活信号。
