Implication of the Toll-Like Receptor 4 Pathway in the Response to Interferon-β in Multiple Sclerosis
Implication of the Toll-Like Receptor 4 Pathway in the Response to Interferon-β in Multiple Sclerosis
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DOI：
10.1002/ana.22511
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发表时间：
2011-10-01
影响因子：
11.2
通讯作者：
Comabella, Manuel
中科院分区：
文献类型：
--
作者：
Bustamante, Marta F.;Fissolo, Nicolas;Comabella, Manuel
目的：干扰素-β（IFN β）已被证明在多发性硬化（MS）患者中具有降低疾病活动性的有益作用，但相对较大比例的患者对治疗无反应。在这里，我们的目的是研究Toll样受体4（TLR 4）和I型IFN途径在MS患者对IFN β的反应中的作用。通过流式细胞术和实时聚合酶链反应（PCR）测定外周血单个核细胞（PBMC）中TLR 4和I型IFN途径的几种组分的表达水平。来自用IFN β治疗至少2年的85名MS患者的队列，并根据其对治疗的临床反应分为反应者、中间反应者和无反应者。32名健康对照也包括在该研究中进行比较purposes.Results：相比，响应者和对照，PBMCs从无应答者和中间应答者的特点是增加的内源性IFN β的基线表达水平和升高的IFN受体1（IFNAR 1）在单核细胞中的表达。此外，与应答者相比，无应答者细胞中IFN β诱导自身表达的能力不足。基线表达的白细胞介素-1受体相关激酶3（IRAK 3），TLR 4信号主要在单核细胞中表达的负调节，被发现是显着降低IFN β responses相比nonresponses.Interpretation：这些研究结果提供了证据的参与的TLR 4和I型IFN信号通路在响应IFN β。神经网络2011;70：634-645
Objective: Interferon-beta (IFN beta) has demonstrated beneficial effects reducing disease activity in multiple sclerosis (MS) patients, but a relatively large proportion of patients do not respond to treatment. Here we aimed to investigate the roles of the Toll-like receptor 4 (TLR4) and the type I IFN pathways in the response to IFN beta in MS patients.Methods: The expression levels of several components of the TLR4 and the type I IFN pathways were determined by flow cytometry and real-time polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMCs) from a cohort of 85 MS patients treated for at least 2 years with IFN beta and classified into responders, intermediate responders, and nonresponders based on their clinical response to treatment. Thirty-two healthy controls were also included in the study for comparison purposes.Results: Compared to responders and controls, PBMCs from nonresponders and intermediate responders were characterized by increased baseline expression levels of endogenous IFN beta and elevated IFN receptor 1 (IFNAR1) expression in monocytes. Furthermore, the capacity of IFN beta to induce its own expression was deficient in cells from nonresponders compared with responders. Baseline expression of the interleukin-1 receptor-associated kinase 3 (IRAK3), a negative regulator of TLR4 signaling primarily expressed in monocytes, was found to be significantly decreased in IFN beta responders compared with nonresponders.Interpretation: These findings provide evidence of the involvement of the TLR4 and type I IFN signaling pathways in the response to IFN beta. ANN NEUROL 2011;70:634-645