NF-kappaB mediated glucocorticoid response in the inner ear after acoustic trauma.
The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10-30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre-treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25-60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF-kappaB, whereas pre-treatment with the drugs (metyrapone and RU 486) blocked NF-kappaB nuclear transport into spiral ganglion nuclei. An NF-kappaB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma-induced translocation of NF-kappaB and resulted in a hearing loss (45-60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF-kappaB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Yeasmin
Y
Tahera
Inna
I
Meltser
Peter
P
Johansson
Zhao
Z
Bian
Pontus
P
Stierna
Anita C
AC
Hansson
Barbara
B
Canlon
D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D015152:Blotting, Northern / Q000379:methods; D004195:Disease Models, Animal; D004347:Drug Interactions; D007758:Ear, Inner / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy* / Q000201:enzymology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D015735:Mifepristone / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013136:Spiral Ganglion / Q000166:cytology; D013997:Time Factors
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D016328:NF-kappa B; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D008797:Metyrapone