Immune-mediated sensorineural hearing loss (IMSNHL) is of clinical importance because ofprogressive bilateral involvement and potential reversibility. Currently, the therapeutic targets specific toIMSNHL are not available because its molecular pathogenesis is poorly understood. Our long-term goal is toelucidate the molecular mechanism of immune-mediated inner ear damage, resulting in SNHL. Etiopathogenesis of IMSNHL is largely unknown, but regardless of the initiating factors, the final courseof IMSNHL is commonly associated with immune-mediated damage of the cochlear cells (sensory and non-sensory). Immune-mediated tissue damage generally involves direct cell-cell signaling via surface moleculessuch as antibody-dependent cytotoxicity; and indirect signaling via cytokines such as tumor necrosis factor-a(TNF-a). Previously, we have demonstrated that spiral ligament fibrocytes (SLFs) release mediators in responseto inflammatory signals and SLF-derived molecules directly attract the inflammatory cells. Therefore, wehypothesize that SLFs are key players in immune-mediated inner ear damage by responding to inflammatorymediators and releasing chemoattractive and cytotoxic molecules. We also found that secretion of TNF-a isrequired for cisplatin-induced ototoxicity and that down-regulation of TNF-a attenuates cisplatin-inducedauditory damage. These results led us to focus on TNF-a-mediated cytotoxicity as a mechanism of immune-mediated inner ear damage. However, the auditory sensory cells appeared to be damaged only by the extremely high concentrationof TNF-a in animal experiments, indicating the requirement of sensitization for TNF-a-mediated inner earcytotoxicity. Therefore, we aim to determine the molecular mechanism involved in: (1) SLF's TNF-a inductionin response to IL-1, a model inflammatory mediator; and (2) sensitization of the auditory sensory cells to induceTNF-a-mediated cytotoxicity via interferon-g (IFN-g). In addition, we plan to determine the therapeutic potentialof targeting the key molecules involved in IFN-g-sensitized TNF-a-mediated cytotoxicity, which will provide uswith a scientific basis for the development of a novel strategy to manage IMSNHL.
The purpose of this project is to determine the molecular mechanism involved in: (1) spiral ligamentfibrocyte's tumor necrosis factor-alpha (TNF-a) induction; and (2) sensitization of the auditory sensory cells forTNF-a-mediated cytotoxicity via Interferon-gamma. In addition; we plan to determine a therapeutic potential oftargeting the key molecules involved in TNF-a-mediated cytotoxicity for the management of immune-mediatedsensorineural hearing loss.
|Woo, Jeong-Im; Kil, Sung-Hee; Pan, Huiqi et al. (2014) Distal NF-kB binding motif functions as an enhancer for nontypeable H. influenzae-induced DEFB4 regulation in epithelial cells. Biochem Biophys Res Commun 443:1035-40|