title: Expression of tumor necrosis factor-α and interleukin-1β genes in the cochlea and inferior colliculus in salicylate-induced tinnitus.
abstract: BACKGROUND
  Changes in the gene expressions for tumor necrosis factor-α (TNF-α) and/or interleukin-1β (IL-1β) during tinnitus have not been previously reported. We evaluated tinnitus and mRNA expression levels of TNF-α, IL-1β, and N-methyl D-aspartate receptor subunit 2B (NR2B) genes in cochlea and inferior colliculus (IC) of mice after intraperitoneal injections of salicylate.
  
  
  METHODS
  Forty-eight 3-month-old male SAMP8 mice were randomly and equally divided into two groups: salicylate-treated and saline-treated. All mice were trained to perform an active avoidance task for 5 days. Once conditioned, an active avoidance task was performed 2 hours after daily intraperitoneal injections of saline, either alone or containing 300 mg/kg sodium salicylate. Total numbers of times (tinnitus score) the mice climbed during the inter-trial silent period for 10 trials were recorded daily for 4 days (days 7 to 10), and then mice were euthanized for determination of mRNA expression levels of TNF-α, IL-1β, and NR2B genes in cochlea and IC at day 10.
  
  
  RESULTS
  Tinnitus scores increased in response to daily salicylate treatments. The mRNA expression levels of TNF-α increased significantly for the salicylate-treated group compared to the control group in both cochlea (1.89 ± 0.22 vs. 0.87 ± 0.07, P < 0.0001) and IC (2.12 ± 0.23 vs. 1.73 ± 0.22, p = 0.0040). mRNA expression levels for the IL-1β gene also increased significantly in the salicylate group compared to the control group in both cochlea (3.50 ± 1.05 vs. 2.80 ± 0.28, p < 0.0001) and IC (2.94 ± 0.51 versus 1.24 ± 0.52, p = 0.0013). Linear regression analysis revealed a significant positive association between tinnitus scores and expression levels of TNF-α, IL-1β, and NR2B genes in cochlea and IC. In addition, expression levels of the TNF-α gene were positively correlated with those of the NR2B gene in both cochlea and IC; whereas, the expression levels of the IL-1β gene was positively correlated with that of the NR2B gene in IC, but not in cochlea.
  
  
  CONCLUSIONS
  We conclude that salicylate treatment resulting in tinnitus augments expression of the TNF-α and IL-1β genes in cochlea and IC of mice, and we suggest that these proinflammatory cytokines might lead to tinnitus directly or via modulating the NMDA receptor.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Juen-Haur
authors.initials: JH
authors.lastname: Hwang
authors.forename: Jin-Cherng
authors.initials: JC
authors.lastname: Chen
authors.forename: Shan-Ying
authors.initials: SY
authors.lastname: Yang
authors.forename: Ming-Fu
authors.initials: MF
authors.lastname: Wang
authors.forename: Yin-Ching
authors.initials: YC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003051:Cochlea / Q000502:physiology*; D003213:Conditioning, Psychological; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007245:Inferior Colliculi / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology / Q000633:toxicity*; D014012:Tinnitus / Q000139:chemically induced* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D012459:Salicylates; D014409:Tumor Necrosis Factor-alpha