TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity
TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity
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DOI：
10.1172/jci200215606
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发表时间：
2002-09-01
影响因子：
15.9
通讯作者：
Reeves, WB
中科院分区：
文献类型：
--
作者：
Ramesh, G;Reeves, WB
这些研究的目的是研究细胞因子在顺铂肾毒性发病机制中的作用。给小鼠注射顺铂（20mg /kg）可导致严重的肾功能衰竭。采用核糖核酸酶保护实验和RT-PCR检测肾组织中细胞因子、趋化因子和ICAM-1的表达。我们发现顺铂治疗动物肾脏中tnf - α、tgf - β、RANTES、MIP-2、MCP-1、TCA3、il -1 β和ICAM-1的显著上调。此外，血清、肾脏和尿液中tnf - α的ELISA检测结果显示顺铂组升高。tnf - α生成抑制剂（GM6001、己酮茶碱）和tnf - α Ab降低了血清和肾脏tnf - α蛋白水平，也减弱了顺铂诱导的tnf - α、tgf - β、RANTES、MIP-2、MCP-1和il -1 β的升高，但对ICAM-1 mRNA没有作用。此外，tnf。抑制剂还可以改善顺铂诱导的肾功能障碍，减少顺铂诱导的结构损伤。同样，tnf - α缺陷小鼠对顺铂肾毒性具有抗性。这些结果表明，顺铂的肾毒性以促炎细胞因子和趋化因子的激活为特征。tnf - α似乎在这种细胞因子反应的激活以及顺铂肾损伤的发病机制中起着核心作用。
The purpose of these studies was to examine the role of cytokines in the pathogenesis of cisplatin nephrotoxicity. Injection of mice with cisplatin (20 mg/kg) led to severe renal failure. The expression of cytokines, chemokines, and ICAM-1 in kidney was measured by ribonuclease protection assays and RT-PCR. We found significant upregulation of TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, TCA3, IL-1beta, and ICAM-1 in kidneys from cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-alpha measured by ELISA were increased by cisplatin. Inhibitors of TNF-alpha production (GM6001, pentoxifylline) and TNF-alpha Ab's reduced serum and kidney TNF-alpha protein levels and also blunted the cisplatin-induced increases in TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, and IL-1beta, but not ICAM-1, mRNA. In addition, the TNF-alpha. inhibitors also ameliorated cisplatin-induced renal dysfunction and reduced cisplatin-induced structural damage. Likewise, TNF-alpha-deficient mice were resistant to cisplatin nephrotoxicity. These results indicate cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-alpha appears to play a central role in the activation of this cytokine response and also in the pathogenesis of cisplatin renal injury.