Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Hyung Jin Kim, Gi Su Oh, Jeong Han Lee, Ah Ra Lyu, Hye Min Ji, Sang Heon Lee, Jeho Song, Sung Joo Park, Yong Ouk You, Jeong Dug Sul, Channy Park, Sang Young Chung, Sung Kyun Moon, David J. Lim, Hong Seob So, Raekil Park

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4-/-, but not in STAT6-/- mice. Moreover, the expression levels of the protein and mRNA of pro-inflammatory cytokines, including TNF-α, IL-1Β, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4-/-, but not STAT6-/- mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6-/- mice were intact after treatment with cisplatin, whereas those from WT and STAT4-/- mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.

Original languageEnglish (US)
Pages (from-to)944-956
Number of pages13
JournalCell Research
Volume21
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • STAT
  • apoptosis
  • cisplatin
  • inflammation
  • ototoxicity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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