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Volume 21, No 6, Jun 2011

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 21 Issue 6, June 2011: 944-956

ORIGINAL ARTICLES

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Hyung-Jin Kim1, Gi-Su Oh1, Jeong-Han Lee1, Ah-Ra Lyu1, Hye-Min Ji1, Sang-Heon Lee2, Jeho Song3, Sung-Joo Park4, Yong-Ouk You5, Jeong-Dug Sul6, Channy Park7, Sang-Young Chung8, Sung-Kyun Moon9, David J Lim9, Hong-Seob So1 and Raekil Park1

1Vestibulocochlear Research Center & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Korea;

2Department of Otolaryngology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Korea;

3Department of Beauty Design, Wonkwang University, Iksan, Jeonbuk 570-749, Korea;

4Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Korea;

5Department of Oral Biochemistry, School of Dentistry, Wonkwang University, Iksan, Jeonbuk 570-749, Korea;

6College of Sport Science, Chung-Ang University, Seoul, Korea;

7Department of Audiology, Nambu University, Gwangju 506-824, Korea;

8Department of Surgery, Chonnam National University Medical School, Gwangju 560-182, Korea;

9Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, CA 90057, USA Correspondence: Hong-Seob So, Raekil Park,(jeanso@wku.ac.kr; rkpark@wku.ac.kr)

>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.


Cell Research (2011) 21:944-956. doi:10.1038/cr.2011.27; published online 22 February 2011

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