Tumor necrosis factor alpha can induce recruitment of inflammatory cells to the cochlea.
OBJECTIVE
Leukocyte recruitment to the cochlea can be induced by tumor necrosis factor alpha (TNF-alpha) at concentrations that are not cytotoxic to sensory cells in the organ of Corti.


BACKGROUND
Leukocytes participating in inflammation enter the inner ear via the spiral modiolar vein and its tributaries. Many of the infiltrated leukocytes express TNF-alpha 3 hours after cochlear antigen challenge of systemically antigen-sensitized animals. Competitive inhibition of TNF-alpha receptors reduces inflammation and hearing loss in experimentally induced labyrinthitis in guinea pigs and mice. However, TNF-alpha is also potentially cytotoxic, acting through the external apoptotic pathway and TNF-alpha transmembrane, cell surface receptors. It may therefore also participate in the sensory cell degeneration resulting from inflammation.


METHODS
To test for recruitment potential, TNF-alpha or phosphate-buffered saline was infused into the guinea pig inner ear for 2 to 4 days through a cochleostomy using an osmotic pump (0.2 or 2.0 microg/mL; 1 microL/h) or a bolus injection (50 microg/mL; 10 microL). Auditory evoked brainstem response thresholds were measured before and after challenge, and cochleas were evaluated for the presence of leukocytes. To test for toxicity, organ of Corti explants were subjected to 3 concentrations of TNF-alpha (0.1, 10, and 1,000 ng/mL) for 96 hours, and the number of hair cell places was counted.


RESULTS
Tumor necrosis factor alpha infused into the guinea pig cochlear scala tympani resulted in infiltration of leukocytes around the venules and within scala tympani. There was no associated hearing loss as measured with a click stimulus. Tumor necrosis factor alpha applied directly to organ of Corti explants caused minimal hair cell death at concentrations used in the in vivo experiments. At higher concentrations, there was 15 to 20% loss of cells.


CONCLUSIONS
Tumor necrosis factor alpha is sufficient to recruit inflammatory cells to the cochlea but is not likely to be directly responsible for the hearing loss that follows immune-mediated labyrinthitis.
Keithley
Elizabeth M
EM
Veterans Affairs Medical Center, La Jolla, California, USA. ekeithley@ucsd.edu
Wang
Xiaobo
X
Barkdull
Gregory C
GC
D000818:Animals; D000831:Animals, Newborn; D003051:Cochlea / Q000187:drug effects*; D006198:Hair Cells, Auditory / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects*; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha