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- Title
Cisplatin ototoxicity involves cytokines and STAT6 signaling network.
- Authors
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
- 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.
- Subjects
CYTOLOGICAL research; CISPLATIN; ANTINEOPLASTIC agents; COORDINATION compounds; METAL-ammonia compounds; HEARING disorders; IMMUNOREGULATION
- Publication
Cell Research, 2011, Vol 21, Issue 6, p944
- ISSN
1001-0602
- Publication type
Article
- DOI
10.1038/cr.2011.27