Department of Pharmacology, School of Medicine, Catholic University of Daegu, Republic of Korea.
Chemosphere. 2010 Nov;81(8):1039-44. doi: 10.1016/j.chemosphere.2010.08.045. Epub 2010 Sep 16.
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-δ showed the most sensitive translocation. The translocation was then blocked by ROS inhibitors (trolox and N-acetyl cysteine), a PKC-δ inhibitor (rottlerin), a caspase-3 inhibitor (z-DEVD-fmk) or an AhR blocker (α-naphthoflavone). TCDD increased caspase-3 activity, the activating enzyme for PKC-δ, and prior treatment with trolox blocked such an increase. These results suggest that the translocation of PKC-δ was mediated by ROS-dependent caspase-3 activity. Pretreatment with rottlerin or trolox dampened TCDD-induced 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-δ mediates the apoptotic processes through ROS-dependent caspase-3 activation. This is a first finding demonstrating the role of PKC-δ 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.
二恶英类化合物的暴露与人类关节炎有关。最近的一项研究报告称，2,3,7,8-四氯二苯并对二恶英（TCDD）诱导软骨细胞凋亡，这是软骨病发病机制中的一个关键事件。在这项研究中，研究了蛋白激酶 C（PKC）信号通路，以确定 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 同工型的易位。在所测试的 PKC 同工型中，PKC-δ 显示出最敏感的易位。然后，通过 ROS 抑制剂（trolox 和 N-乙酰半胱氨酸）、PKC-δ 抑制剂（rottlerin）、caspase-3 抑制剂（z-DEVD-fmk）或 AhR 阻断剂（α-萘黄酮）阻断易位。TCDD 增加了 caspase-3 活性，PKC-δ 的激活酶，而 trolox 的预先处理则阻止了这种增加。这些结果表明 PKC-δ 的易位是由 ROS 依赖性 caspase-3 活性介导的。用 rottlerin 或 trolox 预处理可减弱 TCDD 诱导的软骨细胞凋亡，如 TUNEL 染色和 ELISA 所示。总之，这项研究表明，ROS 的产生是 TCDD 诱导软骨细胞凋亡的上游事件，PKC-δ 通过 ROS 依赖性 caspase-3 激活介导凋亡过程。这是首次证明 PKC-δ 在环境污染物刺激的软骨细胞凋亡中发挥作用的研究。这些结果可能有助于理解与二恶英类化合物暴露相关的关节疾病的机制，并确定治疗干预的靶标。
