IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.
IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease.
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IL-1β在患有自身免疫性内耳疾病的皮质类固醇无反应器中受到过表达和异常调节。
DOI：
10.4049/jimmunol.1002275
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Vambutas A
中科院分区：
文献类型：
--
作者：
Pathak S;Goldofsky E;Vivas EX;Bonagura VR;Vambutas A
自身免疫性内耳疾病是一种神秘的疾病，其特征是反复发作的突然或进行性感音神经性听力损失。及时给予皮质类固醇可以改善听力损失，但只有一半的治疗者有反应，而且对于许多反应者来说，这种反应会随着时间的推移而消失。在这种疾病中控制皮质类固醇反应的机制在很大程度上是未知的。我们之前已经发现，地塞米松诱导 PBMC 中 II 型 IL-1R (IL-1R2) 的表达可以预测这种疾病的皮质类固醇反应。在这项研究中，我们询问 IL-1β 是否过度表达，以及与无反应者相比，临床皮质类固醇反应者是否因地塞米松反应而差异调节 IL-1β 表达或释放。据报道，IL-1β 可诱导基质金属蛋白酶 9 (MMP-9) 表达。鉴于金属蛋白酶可以裂解 IL-1R2，我们还询问 MMP-9 表达是否在这种疾病中发生了改变。在这项研究中，我们证明，与临床有反应的患者相比，皮质类固醇无反应者的血浆 IL-1β 和 MMP-9 水平升高（分别为 p = 0.0008 和 p = 0.037）。 MMP-9 表达的增加与 IL-1β 浓度的增加相关，表明 IL-1β 表达调节 MMP-9 的表达。正如预期的那样，单核细胞是 IL-1β 的主要产生者。 PBMC 体外暴露于临床皮质类固醇反应者的地塞米松可抑制 IL-1β 释放。皮质类固醇无反应者的 PBMC 向条件培养基中释放的 IL-1β 明显较高，并且当暴露于地塞米松时，无法抑制 IL-1β 释放 (p = 0.05)。用阿那白滞素治疗临床皮质类固醇无反应者的 PBMC 导致 IL-1β 释放受到抑制，表明 IL-1β 阻断可能是这些患者的可行疗法。
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 non-responders with anakinra resulted in repression of IL-1β release, suggesting that IL-1β blockade may be a viable therapy for these patients.
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DOI：
10.1016/j.jaci.2008.07.007
发表时间：
2008-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Goleva E;Hauk PJ;Hall CF;Liu AH;Riches DW;Martin RJ;Leung DY
通讯作者：
Leung DY
组蛋白脱乙酰基酶2介导的糖皮质激素受体的脱乙酰基化可以抑制NF-kappab。
影响因子：
15.3
作者：
Ito, Kazuhiro;Yamamura, Satoshi;Essilfie-Quaye, Sarah;Cosio, Borja;Ito, Misako;Barnes, Peter J;Adcock, Ian M
通讯作者：
Adcock, Ian M
影响因子：
3.7
作者：
Hu W;Metselaar J;Ben LH;Cravens PD;Singh MP;Frohman EM;Eagar TN;Racke MK;Kieseier BC;Stüve O
通讯作者：
Stüve O
影响因子：
4.8
作者：
Charron, Catherine E.;Chou, Pai-Chien;Ito, Kazuhiro
通讯作者：
Ito, Kazuhiro
影响因子：
--
作者：
Hawkins, PN;Lachmann, HJ;McDermott, MF
通讯作者：
McDermott, MF