Skip to main content
NCBI home page
JARO: Journal of the Association for Research in Otolaryngology logoLink to JARO: Journal of the Association for Research in Otolaryngology
. 2002 Nov 5;4(2):139–147. doi: 10.1007/s10162-002-3025-7

Proinflammatory Cytokine Expression in the Endolymphatic Sac During Inner Ear Inflammation

Hitoshi Satoh 1, Gary S Firestein 2, Peter B Billings 1, Jeffrey P Harris 1,3, Elizabeth M Keithley 1,3,✉
PMCID: PMC3202716  PMID: 12943369

Abstract

The inner ear is capable of rapidly mounting an immune response that can ultimately lead to cochlear degeneration and permanent hearing loss. The role of the endolymphatic sac in this immune process is not clear. In order to investigate the cytokine expression of cells within the endolymphatic sac, a secondary inner ear immune response to keyhole limpet hemocyanin (KLH) was created in mice. The animals were sacrificed 3–48 h and 7 days following initiation of the immune response. The cochleas and endolymphatic sacs were assayed by immunocytochemistry for IL-1β, TNFα, and IL-6. Three hours after KLH challenge of the scala tympani, the perisaccular tissue of the endolymphatic sac contained more inflammatory cells than the scala tympani or endolymphatic sac lumen. Only a few of these cells, however, expressed the proinflammatory cytokines IL-1β and TNFα between 3 and 12 h after KLH injection. On the other hand, TNFα, which plays an important role in the cochlear secondary immune response, was expressed in cells in the endolymphatic sac lumen. The maximum percentage of cells expressing TNFα was seen later than in the scala tympani. Animals treated with systemic injection of the TNF blocker, etanercept, showed a reduction in the number of cells in the endolymphatic sac lumen. It is concluded that the cells in the endolymphatic sac lumen contribute to the amplification of the adaptive immune response by expressing TNFα, while the infiltration of cells into the perisaccular connective tissue is part of the nonspecific, innate, cochlear immune response.

Keywords: inner ear immunity, cochlear inflammation, innate immunity

Full Text

The Full Text of this article is available as a PDF (227.4 KB).

Acknowledgements

This work was supported by NIH, NIDCD DC04268, The American Otological Society, and the Medical Research Service of the U.S. Department of Veterans Affairs.

References

  • 1.Adams JC. Clinical implications of inflammatory cytokines in the cochlea. Otol. Neurotol. 2002;23:316–322. doi: 10.1097/00129492-200205000-00015. [DOI] [PubMed] [Google Scholar]
  • 2.Chen M-C, Harris JP, Keithley EM. Immunohistochemical analysis of proliferating cells in a sterile labyrinthitis animal model. Laryngoscope. 1998;108:651–656. doi: 10.1097/00005537-199805000-00005. [DOI] [PubMed] [Google Scholar]
  • 3.Harris JP. Immunology of the inner ear: Evidence of local antigen production. Ann. Otol. Rhinol. Laryngol. 1984;93:158–162. doi: 10.1177/000348948409300211. [DOI] [PubMed] [Google Scholar]
  • 4.Iwai H, Tomoda K, Sugiura K, Inaba M, Ikehara S, Yamashita T. T cells infiltrating from the systemic circulation proliferate in the endolymphatic sac. Ann. Otol. Rhinol. Laryngol. 1999;108:1146–1150. doi: 10.1177/000348949910801209. [DOI] [PubMed] [Google Scholar]
  • 5.Juhn SK. The nature of blood labyrinth barrier in experimental conditions. Ann. Otol. Rhinol. Laryngol. 1981;90:135–141. doi: 10.1177/000348948109000208. [DOI] [PubMed] [Google Scholar]
  • 6.Kanzaki J, Ouchi T. Steroid-responsive bilateral sensorineural hearing loss and immune complexes. Arch. Otolaryngol. 1981;230:5–9. doi: 10.1007/BF00665374. [DOI] [PubMed] [Google Scholar]
  • 7.Kawauchi H, Ichimiya I, Kaneda N, Mogi G. Distribution of immunocompetent cells in the endolymphatic sac. Ann. Otol. Rhinol. Laryngol. 1992;101:39–47. doi: 10.1177/0003489492101s1009. [DOI] [PubMed] [Google Scholar]
  • 8.Ma C-L, Billings PB, Harris JP, Keithley EM. Characterization of an experimentally induced inner ear immune response: Laryngoscope. 2000;110:451–456. doi: 10.1097/00005537-200003000-00024. [DOI] [PubMed] [Google Scholar]
  • 9.McCabe BF. Autoimmune sensorineural hearing loss. Ann. Otol. Rhinol. Laryngol. 1992;88:585–589. doi: 10.1177/000348947908800501. [DOI] [PubMed] [Google Scholar]
  • 10.Rask-Andersen H, Stahle J. Lymphocyte–macrophage activity in the endolymphatic sac. An ultrastructural study of the rugose endolymphatic sac in the guinea pig. ORL J. Otorhinolaryngol. Relat. Spec. 1979;41:177–192. doi: 10.1159/000275458. [DOI] [PubMed] [Google Scholar]
  • 11.Rask-Andersen H, Stahle J. Immunodefence of the inner ear? Lymphocyte–macrophage interaction in the endolymphatic sac. Acta Otolaryngol. Stockh. 1980;89:283–294. doi: 10.3109/00016488009127140. [DOI] [PubMed] [Google Scholar]
  • 12.Rask-Andersen H, Bagger–Sjoback D, Lundquist PG. The fenestrated blood vessels of the endolymphatic sac. A freeze-fracture and transmission electron microscopic study. Am. J. Otol. 1983;4:214–221. [PubMed] [Google Scholar]
  • 13.Satoh H. Anti-glomerular basement membrane antibody-induced inflammation in rat cochlear plexus. Acta Otolaryngol. (Stockh.) 1997;117:80–86. doi: 10.3109/00016489709117996. [DOI] [PubMed] [Google Scholar]
  • 14.Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM. TNFα as an initiator and etanercept as a potential therapeutic inhibitor of inner ear inflammation. Laryngoscope. 2002;112:1627–1634. doi: 10.1097/00005537-200209000-00019. [DOI] [PubMed] [Google Scholar]
  • 15.Takahashi M, Harris JP. Anatomic distribution and localization of immunocompetent cells in normal mouse endolymphatic sac. Acta Otolaryngol. (Stockh.) 1988a;106:409–416. doi: 10.3109/00016488809122264. [DOI] [PubMed] [Google Scholar]
  • 16.Takahashi M, Harris JP. Analysis of immunocompetent cells following inner ear immunostimulation. Laryngoscope. 1988b;98:1133–1138. doi: 10.1288/00005537-198810000-00018. [DOI] [PubMed] [Google Scholar]
  • 17.Takahashi M, Tomiyama S. Cell proliferation in the endolymphatic sac in situ after inner ear immunostimulation. Acta Otolaryngol. (Stockh.) 1995;115:396–399. doi: 10.3109/00016489509139336. [DOI] [PubMed] [Google Scholar]
  • 18.Tomiyama S, Harris JP. The endolymphatic sac: its importance in inner ear immune responses. Laryngoscope. 1986;96:685–691. doi: 10.1288/00005537-198606000-00018. [DOI] [PubMed] [Google Scholar]
  • 19.Tomiyama S, Harris JP. The role of the endolymphatic sac in inner ear immunity. Acta Otolaryngol. (Stockh.) 1987;103:182–188. [PubMed] [Google Scholar]
  • 20.Tomiyama S, Harris JP. Elevation of inner ear antibody levels following direct antigen challenge of the endolymphatic sac. Acta Otolaryngol. (Stockh.) 1989;107:202–209. doi: 10.3109/00016488909127499. [DOI] [PubMed] [Google Scholar]
  • 21.Wang X, Billings PB, Firestein GS, Harris JP, Keithley EM. Application of Enbrel in experimental immune-mediated sensorineural hearing loss. Assoc. Res. Otolaryngol. Abstr. 2002;25:92. [Google Scholar]
  • 22.Yeo SW, Gotteschlich S, Harris JP, Keithley EM. Antigen diffusion from the perilymphatic space of the cochlea. Laryngoscope. 1995;105:623–628. doi: 10.1288/00005537-199506000-00012. [DOI] [PubMed] [Google Scholar]
  • 23.Yimtae K, Song H, Billings P, Harris JP, Keithley EM. Connection between the inner ear and the lymphatic system. Laryngoscope. 2001;111:1631–1635. doi: 10.1097/00005537-200109000-00026. [DOI] [PubMed] [Google Scholar]

Articles from JARO: Journal of the Association for Research in Otolaryngology are provided here courtesy of Association for Research in Otolaryngology

RESOURCES