Immune-mediated sensorineural hearing loss (IMSNHL) is of clinical importance because of progressive bilateral involvement and potential reversibility. Currently, the therapeutic targets specific to IMSNHL are not available because its molecular pathogenesis is poorly understood. Our long-term goal is to elucidate 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 course of 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 molecules such as antibody-dependent cytotoxicity;and indirect signaling via cytokines such as tumor necrosis factor-( (TNF-(). Previously, we have demonstrated that spiral ligament fibrocytes (SLFs) release mediators in response to inflammatory signals and SLF-derived molecules directly attract the inflammatory cells. Therefore, we hypothesize that SLFs are key players in immune-mediated inner ear damage by responding to inflammatory mediators and releasing chemoattractive and cytotoxic molecules. We also found that secretion of TNF-( is required for cisplatin-induced ototoxicity and that down-regulation of TNF-( attenuates cisplatin-induced auditory damage. These results led us to focus on TNF-(-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 concentration of TNF-( in animal experiments, indicating the requirement of sensitization for TNF-(-mediated inner ear cytotoxicity. Therefore, we aim to determine the molecular mechanism involved in: (1) SLF's TNF-( induction in response to IL-1, a model inflammatory mediator;and (2) sensitization of the auditory sensory cells to induce TNF-(-mediated cytotoxicity via interferon-( (IFN-(). In addition, we plan to determine the therapeutic potential of targeting the key molecules involved in IFN-(-sensitized TNF-(-mediated cytotoxicity, which will provide us with a scientific basis for the development of a novel strategy to manage IMSNHL.

Public Health Relevance

The purpose of this project is to determine the molecular mechanism involved in: (1) spiral ligament fibrocyte's tumor necrosis factor-alpha (TNF-() induction;and (2) sensitization of the auditory sensory cells for TNF-(-mediated cytotoxicity via Interferon-gamma. In addition, we plan to determine a therapeutic potential of targeting the key molecules involved in TNF-(-mediated cytotoxicity for the management of immune-mediated sensorineural hearing loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZDC1-SRB-Y (52))
Program Officer
Watson, Bracie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
House Research Institute
Los Angeles
United States
Zip Code
Mwangi, Martin; Kil, Sung-Hee; Phak, David et al. (2017) Interleukin-10 Attenuates Hypochlorous Acid-Mediated Cytotoxicity to HEI-OC1 Cochlear Cells. Front Cell Neurosci 11:314
Woo, Jeong-Im; Kil, Sung-Hee; Brough, Douglas E et al. (2015) Therapeutic potential of adenovirus-mediated delivery of ?-defensin 2 for experimental otitis media. Innate Immun 21:215-24
Woo, Jeong-Im; Kil, Sung-Hee; Oh, Sejo et al. (2015) IL-10/HMOX1 signaling modulates cochlear inflammation via negative regulation of MCP-1/CCL2 expression in cochlear fibrocytes. J Immunol 194:3953-61
Woo, Jeong-Im; Oh, Sejo; Webster, Paul et al. (2014) NOD2/RICK-dependent ?-defensin 2 regulation is protective for nontypeable Haemophilus influenzae-induced middle ear infection. PLoS One 9:e90933
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
Li, Jian-Dong; Hermansson, Ann; Ryan, Allen F et al. (2013) Panel 4: Recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models. Otolaryngol Head Neck Surg 148:E52-63
Oh, Sejo; Woo, Jeong-Im; Lim, David J et al. (2012) ERK2-dependent activation of c-Jun is required for nontypeable Haemophilus influenzae-induced CXCL2 upregulation in inner ear fibrocytes. J Immunol 188:3496-505
Lim, David J; Moon, Sung K (2011) Establishment of cell lines from the human middle and inner ear epithelial cells. Adv Exp Med Biol 720:15-25
Woo, Jeong-Im; Pan, Huiqi; Oh, Sejo et al. (2010) Spiral ligament fibrocyte-derived MCP-1/CCL2 contributes to inner ear inflammation secondary to nontypeable H. influenzae-induced otitis media. BMC Infect Dis 10:314