Calcium-mediated activation of c-jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages
Calcium-mediated activation of c-jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages
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DOI：
10.1093/toxsci/kfh221
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发表时间：
2004-10-01
影响因子：
3.8
通讯作者：
Sharma, RP
中科院分区：
文献类型：
--
作者：
Kim, J;Sharma, RP
镉是一种众所周知的致癌和免疫毒性金属，通常存在于香烟烟雾和工业废水中。细胞内钙（[Ca 2 +]（i））水平的改变与免疫功能障碍的病理生理学有关。本研究旨在确定可能参与的钙（Ca 2+）和丝裂原活化蛋白激酶（MAPKs）信号通路镉诱导的细胞死亡J774A.1小鼠巨噬细胞。镉在20 μ M时引起低幅度的[Ca 2 +]（i）升高，在500 μ M时引起快速和高幅度的[Ca 2 +]（i）升高。暴露于镉剂量依赖性地诱导c-Jun氨基末端激酶（JNK）的磷酸化和失活的p38 MAPK。选择性JNK抑制剂SP 600125的使用表明JNK的活化是促凋亡和促坏死的。用1，2-双-（2-氨基苯氧基）-乙烷-N，N，N ′，N ′-四乙酸四（乙酰氧基-甲基）酯（BAPTA-AM）和乙二醇-双-（β-氨基乙基醚）-N，N，N ′，N ′-四乙酸（EGTA）缓冲钙反应完全阻断镉诱导的凋亡反应。用BAPTA-AM和EGTA预处理细胞可抑制镉诱导的细胞损伤，包括生长停滞、线粒体活性受损和坏死，并恢复镉改变的JNK和p38 MAPK活性。螯合[Ca 2 +]（i）也逆转了镉诱导的过氧化氢生成，表明活性氧（ROS）的产生与[Ca 2 +]（i）有关。本研究表明，镉诱导[Ca 2 +]（i）-ROS-JNK-caspase-3信号通路导致细胞凋亡。此外，镉诱导的[Ca 2 +]（i）调节JNK和p38的磷酸化/去磷酸化，并且其调节增殖、线粒体活性和坏死的信号转导途径。
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 muM and rapid and high-amplitude [Ca2+](i) elevation at 500 muM. 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-(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 [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.