title: Cisplatin ototoxicity involves cytokines and STAT6 signaling network.
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.
authors.affiliation: Vestibulocochlear Research Center & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Korea.
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Ah-Ra
authors.initials: AR
authors.lastname: Lyu
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Ji
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
authors.forename: Jeho
authors.initials: J
authors.lastname: Song
authors.forename: Sung-Joo
authors.initials: SJ
authors.lastname: Park
authors.forename: Yong-Ouk
authors.initials: YO
authors.lastname: You
authors.forename: Jeong-Dug
authors.initials: JD
authors.lastname: Sul
authors.forename: Channy
authors.initials: C
authors.lastname: Park
authors.forename: Sang-Young
authors.initials: SY
authors.lastname: Chung
authors.forename: Sung-Kyun
authors.initials: SK
authors.lastname: Moon
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003603:Cytotoxins / Q000633:toxicity*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D017930:Genes, Reporter; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D034381:Hearing Loss / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D003603:Cytotoxins; D016328:NF-kappa B; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D008156:Luciferases; D002945:Cisplatin