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 language | English (US) |
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Pages (from-to) | 944-956 |
Number of pages | 13 |
Journal | Cell Research |
Volume | 21 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2011 |
Keywords
- STAT
- apoptosis
- cisplatin
- inflammation
- ototoxicity
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology