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Cisplatin ototoxicity involves cytokines and STAT6 signaling network.
- Source :
-
Cell research [Cell Res] 2011 Jun; Vol. 21 (6), pp. 944-56. Date of Electronic Publication: 2011 Feb 15. - Publication Year :
- 2011
-
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 :
- Animals
Apoptosis drug effects
Cell Line
Cell Survival drug effects
Cochlea drug effects
Cochlea pathology
Cytokines genetics
Evoked Potentials, Auditory, Brain Stem drug effects
Genes, Reporter
Hair Cells, Auditory drug effects
Hair Cells, Auditory pathology
Hearing Loss chemically induced
Hearing Loss pathology
Hearing Loss physiopathology
Luciferases biosynthesis
Luciferases genetics
Mice
Mice, Inbred BALB C
Mice, Knockout
NF-kappa B genetics
NF-kappa B metabolism
Phosphorylation
Promoter Regions, Genetic
RNA Interference
STAT4 Transcription Factor genetics
STAT4 Transcription Factor metabolism
STAT6 Transcription Factor genetics
Transcription, Genetic
Antineoplastic Agents toxicity
Cisplatin toxicity
Cytokines metabolism
Cytotoxins toxicity
STAT6 Transcription Factor metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1748-7838
- Volume :
- 21
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell research
- Publication Type :
- Academic Journal
- Accession number :
- 21321603
- Full Text :
- https://doi.org/10.1038/cr.2011.27