PKC-δ mediates TCDD-induced apoptosis of chondrocyte in ROS-dependent manner.
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.
Lee
Hyun-Gyo
HG
Department of Pharmacology, School of Medicine, Catholic University of Daegu, Republic of Korea.
Yang
Jae-Ho
JH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D017382:Reactive Oxygen Species; D051745:Protein Kinase C-delta; D053148:Caspase 3