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

Sung K. Moon, Jeong Im Woo, David J. Lim

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8S-15S
JournalAnnals of Otology, Rhinology and Laryngology
Volume128
Issue number6_suppl
DOIs
StatePublished - Jun 1 2019

Keywords

  • acquired hearing loss
  • cochlear inflammation
  • cytokine
  • ototoxicity
  • sensitization

ASJC Scopus subject areas

  • Otorhinolaryngology

Fingerprint Dive into the research topics of 'Involvement of TNF-α and IFN-γ in Inflammation-Mediated Cochlear Injury'. Together they form a unique fingerprint.

Cite this