Dexamethasone attenuates the TNF-α-induced ototoxicity by Prdx6 upregulation in murine auditory hair cells and cochlea of noise-exposed mice = 청각유모세포와 소음 노출 마우스 내이에서 Dexamethasone의 Prdx6 상향 조절에 따른 TNF-α에 의한 이독성 약화 효과

다국어 초록 (Multilingual Abstract)

Tumor necrosis factor-alpha (TNF-α) is one of the major cytokines that triggers damage to auditory hair cells, exerting sensorineural hearing loss. Dexamethasone (DEX) is widely used to reduce inflammation and is known to upregulate the expression of peroxiredoxin 6 (Prdx6), an antioxidant enzyme. We previously reported that DEX pretreatment protected auditory hair cells from TNF-α-triggered damage. In this study, we investigated the involvement of Prdx6 in the protective effect of DEX on TNF-α-triggered ototoxicity. DEX pretreatment resulted in reduced TNF-α-induced intracellular and mitochondrial reactive oxygen species (ROS) accumulation, pro-inflammatory cytokine expression, and NF-κB signaling activation. The Prdx6 expression level was decreased in TNF-α-treated cells but increased in DEX-treated cells. Moreover, DEX pretreatment elevated the expression of Prdx6 and the glucocorticoid receptor. Chromatin immunoprecipitation and luciferase reporter assays demonstrated transactivation of the Prdx6 gene by DEX pretreatment. In noise-exposed mice, we observed increased auditory brainstem response (ABR) thresholds, decreased numbers of outer hair cells (OHCs), increased expression of TNF-α, IL-1β, and phospho-p65 protein (an NF-κB subunit), and reduced expression of Prdx6 protein. DEX pretreatment prior to noise exposure resulted in a suppressed elevation of ABR threshold and reduced damage to OHCs. Furthermore, intense Prdx6 immunoreactivity and a weaker expression of TNF-α, IL-1β, and p-p65 were observed in cochlear tissues. These findings suggested that DEX pretreatment suppresses ROS- and inflammation-related signaling through transcriptional upregulation of Prdx6, subsequently attenuating TNF-α-triggered ototoxicity.

목차 (Table of Contents)

• Abstract i
• Contents ii
• List of Abbreviations iii
• List of Figures iv
• Introduction 1
• Materials and Methods 4
• Results 12
• Discussion 30
• Conclusion 36
• References 37
• Abstract in Korean 44