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Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages.
Toxicol Sci. 2004 Oct; 81(2):518-27.TS

Abstract

Cadmium is a well-known carcinogenic and immunotoxic metal commonly found in cigarette smoke and industrial effluent. An altered intracellular calcium ([Ca(2+)](i)) level has been implicated in the pathophysiology of immune dysfunction. The present study was designed to determine the possible involvement of calcium (Ca(2+)) and mitogen-activated protein kinases (MAPKs) signaling pathways on cadmium-induced cell death in J774A.1 murine macrophage cells. Cadmium caused a low-amplitude [Ca(2+)](i) elevation at 20 microM and rapid and high-amplitude [Ca(2+)](i) elevation at 500 microM. Exposure to cadmium dose-dependently induced phosphorylation of c-Jun NH(2)-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-(beta-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 [Ca(2+)](i) also reversed cadmium-induced hydrogen peroxide generation, suggesting that production of reactive oxygen species (ROS) is related to [Ca(2+)](i). The present study showed that cadmium induces a [Ca(2+)](i)-ROS-JNK-caspase-3 signaling pathway leading to apoptosis. Furthermore, cadmium-induced [Ca(2+)](i) regulates phosphorylation/dephosphorylation of JNK and p38, and it modulates signal transduction pathways to proliferation, mitochondrial activity, and necrosis.

Authors+Show Affiliations

Interdisciplinary Program of Toxicology, Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15254339

Citation

Kim, Jiyoung, and Raghubir P. Sharma. "Calcium-mediated Activation of c-Jun NH2-terminal Kinase (JNK) and Apoptosis in Response to Cadmium in Murine Macrophages." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 81, no. 2, 2004, pp. 518-27.
Kim J, Sharma RP. Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages. Toxicol Sci. 2004;81(2):518-27.
Kim, J., & Sharma, R. P. (2004). Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages. Toxicological Sciences : an Official Journal of the Society of Toxicology, 81(2), 518-27.
Kim J, Sharma RP. Calcium-mediated Activation of c-Jun NH2-terminal Kinase (JNK) and Apoptosis in Response to Cadmium in Murine Macrophages. Toxicol Sci. 2004;81(2):518-27. PubMed PMID: 15254339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages. AU - Kim,Jiyoung, AU - Sharma,Raghubir P, Y1 - 2004/07/14/ PY - 2004/7/16/pubmed PY - 2005/2/5/medline PY - 2004/7/16/entrez SP - 518 EP - 27 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 81 IS - 2 N2 - Cadmium is a well-known carcinogenic and immunotoxic metal commonly found in cigarette smoke and industrial effluent. An altered intracellular calcium ([Ca(2+)](i)) level has been implicated in the pathophysiology of immune dysfunction. The present study was designed to determine the possible involvement of calcium (Ca(2+)) and mitogen-activated protein kinases (MAPKs) signaling pathways on cadmium-induced cell death in J774A.1 murine macrophage cells. Cadmium caused a low-amplitude [Ca(2+)](i) elevation at 20 microM and rapid and high-amplitude [Ca(2+)](i) elevation at 500 microM. Exposure to cadmium dose-dependently induced phosphorylation of c-Jun NH(2)-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-(beta-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 [Ca(2+)](i) also reversed cadmium-induced hydrogen peroxide generation, suggesting that production of reactive oxygen species (ROS) is related to [Ca(2+)](i). The present study showed that cadmium induces a [Ca(2+)](i)-ROS-JNK-caspase-3 signaling pathway leading to apoptosis. Furthermore, cadmium-induced [Ca(2+)](i) regulates phosphorylation/dephosphorylation of JNK and p38, and it modulates signal transduction pathways to proliferation, mitochondrial activity, and necrosis. SN - 1096-6080 UR - https://www.unboundmedicine.com/medline/citation/15254339/Calcium_mediated_activation_of_c_Jun_NH2_terminal_kinase__JNK__and_apoptosis_in_response_to_cadmium_in_murine_macrophages_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfh221 DB - PRIME DP - Unbound Medicine ER -