title: IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.
abstract: Autoimmune inner ear disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hearing loss. Hearing loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1β was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1β expression or release in response to dexamethasone, as compared with nonresponders. IL-1β has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1β and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1β concentration, suggesting that IL-1β expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1β. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1β release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1β into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1β release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1β release, suggesting that IL-1β blockade may be a viable therapy for these patients.
authors.affiliation: Feinstein Institute for Medical Research, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, NY 11030, USA.
authors.forename: Shresh
authors.initials: S
authors.lastname: Pathak
authors.forename: Elliot
authors.initials: E
authors.lastname: Goldofsky
authors.forename: Esther X
authors.initials: EX
authors.lastname: Vivas
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Bonagura
authors.forename: Andrea
authors.initials: A
authors.lastname: Vambutas
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D019929:Cochlear Implantation; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology*; D005938:Glucocorticoids / Q000627:therapeutic use*; D006319:Hearing Loss, Sensorineural / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors; D011241:Prednisone / Q000627:therapeutic use; D011446:Prospective Studies
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9; D011241:Prednisone