Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF- κ B

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• 作者：Hongseob So ; HyungJin Kim ; Jeong-Han Lee ; Channy Park ; Yunha Kim ; Eunsook Kim ; Jin-Kyung Kim ; Ki-Jung Yun ; Kang-Min Lee and Haa-Yung Lee ; et al.
• 关键词：apoptosis ; inflammation ; TNF ; α ; ototoxic mechanisms
• 刊名：JARO - Journal of the Association for Research in Otolaryngology
• 出版年：2007
• 出版时间：September, 2007
• 年：2007
• 卷：8
• 期：3
• 页码：338-355
• 全文大小：1,101 KB
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Otorhinolaryngology
  Neurosciences
  Neurobiology
  
• 出版者：Springer New York
• ISSN：1438-7573

文摘

The ototoxicity of cisplatin, a widely used chemotherapeutic agent, involves a number of mechanisms, including perturbation of redox status, increase in lipid peroxidation, and formation of DNA adducts. In this study, we demonstrate that cisplatin increased the early immediate release and de novo synthesis of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, through the activation of ERK and NF-κB in HEI-OC1 cells, which are conditionally immortalized cochlear cells that express hair cell markers. Both neutralization of proinflammatory cytokines and pharmacologic inhibition of ERK significantly attenuated the death of HEI-OC1 auditory cells caused by cisplatin and proinflammatory cytokines. We also observed a significant increase in the protein and mRNA levels of proinflammatory cytokines in both serum and cochleae of cisplatin-injected rats, which was suppressed by intraperitoneal injection of etanercept, an inhibitor of TNF-α. Immunohistochemical studies revealed that TNF-α expression was mainly located in the spiral ligament, spiral limbus, and the organ of Corti in the cochleae of cisplatin-injected rats. NF-κB protein expression, which overlapped with terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling-positive signal, was very strong in specific regions of the cochleae, including the organ of Corti, spiral ligament, and stria vascularis. These results indicate that proinflammatory cytokines, especially TNF-α, play a central role in the pathophysiology of sensory hair cell damage caused by cisplatin.