Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons
Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons
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DOI：
10.1016/j.jaci.2014.11.039
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发表时间：
2015-07-01
影响因子：
14.2
通讯作者：
Edwards, Michael R.
中科院分区：
文献类型：
--
作者：
Gielen, Vera;Sykes, Annemarie;Edwards, Michael R.
背景资料：鼻病毒感染是哮喘急性发作的主要原因，并且哮喘患者中IFN-α/β/λ的病毒诱导缺陷在哮喘急性发作发病机制中是重要的。造成这种干扰素缺乏症的哮喘patients.Objective：我们试图探讨抑制细胞因子信号传导（SOCS）1在哮喘患者的组织中的表达及其在受损的病毒诱导的干扰素induction in these patients.Methods：我们评估了SOCS 1的mRNA和蛋白水平在体外，支气管活检标本，和小鼠。SOCS 1的作用是通过使用报告基因过表达和SOCS 1缺陷小鼠的概念验证研究推断的。通过支气管活检染色、突变体SOCS 1构建体的过表达和共聚焦显微镜检查，显示了SOCS 1的核作用。SOCS 1水平也与哮喘相关的临床outcomes.Results：我们报告的诱导SOCS 1在支气管上皮细胞（BECs）的哮喘急性发作相关的细胞因子和鼻病毒感染体外。我们发现SOCS 1在体内支气管上皮中增加，并与哮喘严重程度相关。SOCS 1的表达也增加了原发性BEC哮喘患者离体和相关的干扰素缺乏和病毒复制增加。在原代人上皮细胞，小鼠肺巨噬细胞，SOCS 1缺陷小鼠，SOCS 1抑制鼻病毒诱导的干扰素。病毒诱导的干扰素水平的抑制依赖于SOCS 1核转位，但独立于转录因子的蛋白酶体降解。核SOCS 1水平也增加了BECs从哮喘patient.Conclusion：我们描述了一种新的机制，解释干扰素缺乏症在哮喘患者通过一种新的核功能SOCS 1和确定SOCS 1作为一个重要的治疗目标，哮喘急性发作。
Background: Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-alpha/beta/lambda in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.Objective: We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.Methods: We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.Results: We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.Conclusion: We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.