Involvement of TNF-α and IFN-γ in Inflammation-Mediated Cochlear Injury

Objectives: Inflammation is crucial for the pathogenesis of acquired sensorineural hearing loss, but the precise mechanism involved remains elusive. Among a number of inflammatory mediators, tumor necrosis factor-alpha (TNF-α) plays a pivotal role in cisplatin ototoxicity. However, TNF-α alone is cy...

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Bibliographic Details
Published in:Annals of otology, rhinology & laryngology rhinology & laryngology, 2019-06, Vol.128 (6_suppl), p.8S-15S
Main Authors: Moon, Sung K., Woo, Jeong-Im, Lim, David J.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Cell Culture Techniques
Cell Survival
Cisplatin - pharmacology
Hair Cells, Auditory - drug effects
Hair Cells, Auditory - metabolism
Hair Cells, Auditory - pathology
Inflammation
Inflammation Mediators - metabolism
Interferon-gamma - pharmacology
Mice
Mice, Inbred C57BL
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Objectives: Inflammation is crucial for the pathogenesis of acquired sensorineural hearing loss, but the precise mechanism involved remains elusive. Among a number of inflammatory mediators, tumor necrosis factor-alpha (TNF-α) plays a pivotal role in cisplatin ototoxicity. However, TNF-α alone is cytotoxic to cochlear sensory cells only at the extremely high concentrations, suggesting the involvement of other factors that may sensitize cells to TNF-α cytotoxicity. Since interferon gamma (IFN-γ) importantly contributes to the cochlear inflammatory processes, we aim to determine whether and how IFN-γ affects TNF-α cytotoxicity to cochlear sensory cells. Methods: TNF-α expression was determined with western blotting in RSL cells and immunolabeling of mouse temporal bone sections. HEI-OC1 cell viability was determined with MTT assays, cytotoxicity assays, and cytometric analysis with methylene blue staining. Cochlear sensory cell injury was determined in the organotypic culture of the mouse organ of Corti. Results: Spiral ligament fibrocytes were shown to upregulate TNF-α in response to pro-inflammatory stimulants. We demonstrated IFN-γ increases the susceptibility of HEI-OC1 cells to TNF-α cytotoxicity via JAK1/2-STAT1 signaling. TNFR1-mediated Caspase-1 activation was found to mediate the sensitization effect of IFN-γ on TNF-α cytotoxicity. The combination of IFN-γ and TNF-α appeared to augment cisplatin cytotoxicity to cochlear sensory cells ex vivo. Conclusions: Taken together, these findings suggest the involvement of IFN-γ in the sensitization of cochlear cells to TNF-α cytotoxicity, which would enable us to better understand the complex mechanisms underlying inflammation-mediated cochlear injury.
ISSN:0003-4894
1943-572X
DOI:10.1177/0003489419837689