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Tumor Necrosis Factor-α, an Initiator, and Etanercept, an Inhibitor of Cochlear Inflammation

Authors

  • Hitoshi Satoh MD,

    1. Divisions of Otolaryngology—Head and Neck Surgery, University of California, San Diego, U.S.A.
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  • Gary S. Firestein MD,

    1. Divisions of Rheumatology, Allergy, and Immunology, University of California, San Diego, U.S.A.
    2. Research Service of the Department of Veterans Affairs, San Diego, California, U.S.A.
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  • Peter B. Billings PhD,

    1. Divisions of Otolaryngology—Head and Neck Surgery, University of California, San Diego, U.S.A.
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  • Jeffrey P. Harris MD, PhD,

    1. Divisions of Otolaryngology—Head and Neck Surgery, University of California, San Diego, U.S.A.
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  • Elizabeth M. Keithley PhD

    Corresponding author
    1. Divisions of Otolaryngology—Head and Neck Surgery, University of California, San Diego, U.S.A.
    • Elizabeth M. Keithley, PhD, Division of Otolaryngology—Head and Neck Surgery, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0666, U.S.A.
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  • Presented in part at the Midwinter Meeting of the Association for Research in Otolaryngology, St. Petersburg Beach, FL, February 4, 2001.

  • Supported by NIH, NIDCD DC04268, the American Otologic Society, and the Medical Research Service of the U.S. Department of Veterans Affairs.

Abstract

Objectives/Hypothesis The inner ear rapidly mounts an immune response that can lead to cochlear degeneration and permanent hearing loss. Identification of proinflammatory cytokine expression during the initiation of the response should lead to rational therapeutic strategies that block the response, reducing damaging sequelae.

Study Design A cochlear immune response to keyhole limpet hemocyanin (KLH) injected into the inner ear or subarachnoid space of sensitized animals was created. Etanercept was administered to a group of animals to blunt the immune response.

Methods Cochleae were immunoassayed for expression of interleukin-1β, tumor necrosis factor-α, and interleukin-6 and evaluated for the amount of cochlear-infiltrated cells.

Results Tumor necrosis factor-α and interleukin-1β were expressed by infiltrated cells shortly after KLH injection. Tumor necrosis factor-α was expressed whether the antigen was introduced with or without surgical trauma. Interleukin-1β was also expressed by the cochlear fibrocytes during the immune response and in surgical control animals, but not after intrathecal injection of antigen. Interleukin-6 expression was minimal during the response. Based on this observation, animals were treated with systemic injection of Etanercept, which reduced cochlear infiltrating cell number and cochlear fibrosis.

Conclusion Interleukin-1β expression is a general cochlear response to trauma, whereas tumor necrosis factor-α expression in the infiltrated immunocompetent cells is the cytokine that induces amplification of the response that leads to cochlear disease.

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