ToxSci Advance Access originally published online on July 14, 2004
Toxicological Sciences 2004 81(2):518-527; doi:10.1093/toxsci/kfh221
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Toxicological Sciences vol. 81 no. 2 © Society of Toxicology 2004; all rights reserved.
Calcium-Mediated Activation of c-Jun NH2-Terminal Kinase (JNK) and Apoptosis in Response to Cadmium in Murine Macrophages
Interdisciplinary Program of Toxicology, Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia
Received May 11, 2004; accepted July 2, 2004
Cadmium is a well-known carcinogenic and immunotoxic metal commonly found in cigarette smoke and industrial effluent. An altered intracellular calcium ([Ca2+]i) level has been implicated in the pathophysiology of immune dysfunction. The present study was designed to determine the possible involvement of calcium (Ca2+) and mitogen-activated protein kinases (MAPKs) signaling pathways on cadmium-induced cell death in J774A.1 murine macrophage cells. Cadmium caused a low-amplitude [Ca2+]i elevation at 20 µM and rapid and high-amplitude [Ca2+]i elevation at 500 µM. Exposure to cadmium dose-dependently induced phosphorylation of c-Jun NH2-terminal kinase (JNK) and deactivated p38 MAPK. Use of the selective JNK inhibitor SP600125 suggested that activation of JNK is pro-apoptotic and pro-necrotic. Buffering of the calcium response with 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxy-methyl) ester (BAPTA-AM) and ethylene glycol-bis-(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) completely blocked cadmium-induced apoptotic response. The pretreatment of cells with BAPTA-AM and EGTA suppressed the cadmium-induced cell injury, including growth arrest, mitochondrial activity impairment, and necrosis, and it also recovered the cadmium-altered JNK and p38 MAPK activity. Chelating [Ca2+]i also reversed cadmium-induced hydrogen peroxide generation, suggesting that production of reactive oxygen species (ROS) is related to [Ca2+]i. The present study showed that cadmium induces a [Ca2+]i-ROS-JNK-caspase-3 signaling pathway leading to apoptosis. Furthermore, cadmium-induced [Ca2+]i regulates phosphorylation/dephosphorylation of JNK and p38, and it modulates signal transduction pathways to proliferation, mitochondrial activity, and necrosis.
Key Words: cadmium; calcium; ROS; MAPKs; growth arrest; apoptosis.
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