PKC-δ, mediates TCDD-induced apoptosis of chondrocyte in ROS-dependent manner
PKC-δ, mediates TCDD-induced apoptosis of chondrocyte in ROS-dependent manner
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DOI：
10.1016/j.chemosphere.2010.08.045
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发表时间：
2010-11-01
期刊：
影响因子：
8.8
通讯作者：
Yang, Jae-Ho
中科院分区：
文献类型：
--
作者：
Lee, Hyun-Gyo;Yang, Jae-Ho
暴露于二恶英类化合物与人类关节炎有关。最近一项研究报道，2.3.7,8，-四氯二苯并-对二恶英（TCDD）诱导软骨细胞凋亡是软骨疾病发病的关键事件。本研究通过蛋白激酶C （PKC）信号通路研究tcdd诱导兔关节软骨细胞凋亡的机制。TCDD暴露诱导谷胱甘肽介导的ROS生成和PKC同工酶易位。在所检测的PKC同工酶中，PKC-delta表现出最敏感的易位。然后用ROS抑制剂（trolox和n -乙酰半胱氨酸）、PKC-delta抑制剂（rottlerin）、caspase-3抑制剂（z-DEVD-fmk）或AhR阻滞剂（α -萘黄酮）阻断易位。TCDD增加了pkc - δ的激活酶caspase-3的活性，而之前用trolox治疗阻断了这种增加。这些结果表明PKC-delta的易位是由ros依赖性caspase-3活性介导的。通过TUNEL染色和ELISA检测，鹿特素或trolox预处理对tcdd诱导的软骨细胞凋亡有抑制作用。综上所述，本研究表明，ROS的产生是tcdd诱导的软骨细胞凋亡的上游事件，PKC-delta通过ROS依赖性caspase-3激活介导凋亡过程。这是首次发现PKC-delta在环境污染物刺激的软骨细胞凋亡中的作用。该结果可能有助于了解与暴露于二恶英样化合物相关的关节疾病的机制，并确定治疗干预的目标。(C) 2010 Elsevier Ltd.版权所有。
Exposure to dioxin-like compounds is associated with arthritis in humans. A recent study reported that 2.3.7,8,-tetrachlorodibenzo-p-dioxin (TCDD) induces apoptosis in chondrocytes, which is a critical event in the pathogenesis of cartilage disease. In this study, protein kinase C (PKC) signaling pathway was investigated to determine the mechanism of TCDD-induced rabbit articular chondrocyte apoptosis. TCDD exposure induced glutathione-mediated ROS generation and the translocation of PKC isozymes. Among the PKC isozymes tested, PKC-delta showed the most sensitive translocation. The translocation was then blocked by ROS inhibitors (trolox and N-acetyl cysteine), a PKC-delta inhibitor (rottlerin), a caspase-3 inhibitor (z-DEVD-fmk) or an AhR blocker (alpha-naphthoflavone). TCDD increased caspase-3 activity, the activating enzyme for PKC-delta, and prior treatment with trolox blocked such an increase. These results suggest that the translocation of PKC-delta was mediated by ROS-dependent caspase-3 activity. Pretreatment with rottlerin or trolox dampened TCDD-inducecl apoptosis of chondrocyte, as determined by TUNEL staining and ELISA. Taken together, this study suggests that ROS generation is an upstream event for TCDD-induced chondrocyte apoptosis and PKC-delta mediates the apoptotic processes through ROS-dependent caspase-3 activation. This is a first finding demonstrating the role of PKC-delta in chondrocyte apoptosis stimulated by an environmental pollutant. The results may contribute to understanding the mechanism of joint disease associated with the exposure of dioxin-like compounds and identifying a target for the therapeutic interventions. (C) 2010 Elsevier Ltd. All rights reserved.