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IL-1? 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-1? was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1? expression or release in response to dexamethasone, as compared with nonresponders. IL-1? 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-1? 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-1? concentration, suggesting that IL-1? expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1?. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1? release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1? into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1? release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1? release, suggesting that IL-1? blockade may be a viable therapy for these patients.

SUBMITTER: Pathak S

PROVIDER: S-EPMC3031454 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.

Pathak Shresh S Goldofsky Elliot E Vivas Esther X EX Bonagura Vincent R VR Vambutas Andrea A

Journal of immunology (Baltimore, Md. : 1950) 20110103 3

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 (I ...[more]

PMID: 21199898

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Project description:Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography-tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = -0.487; P < 0.001). In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.

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IL-1? is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.

Publications

IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.

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