Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-κB

Hongseob So, Hyung Jin Kim, Jeong Han Lee, Channy Park, Yunha Kim, Eunsook Kim, Jin Kyung Kim, Ki Jung Yun, Kang Min Lee, Haa Yung Lee, Sung Kyun Moon, David J. Lim, Raekil Park

Research output: Contribution to journalArticle

162 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)338-355
Number of pages18
JournalJARO - Journal of the Association for Research in Otolaryngology
Volume8
Issue number3
DOIs
StatePublished - Sep 2007

Keywords

  • Apoptosis
  • Inflammation
  • Ototoxic mechanisms
  • TNF-α

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Sensory Systems

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