Cisplatin ototoxicity involves cytokines and STAT6 signaling network |
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Authors: | Kim Hyung-Jin Oh Gi-Su Lee Jeong-Han Lyu Ah-Ra Ji Hye-Min Lee Sang-Heon Song Jeho Park Sung-Joo You Yong-Ouk Sul Jeong-Dug Park Channy Chung Sang-Young Moon Sung-Kyun Lim David J So Hong-Seob Park Raekil |
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Institution: | Vestibulocochlear Research Center & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Korea. |
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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. |
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Keywords: | cisplatin ototoxicity STAT inflammation apoptosis |
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