哮喘支气管上皮中细胞因子信号传导抑制因子1的核内表达增加会抑制鼻病毒诱导的先天性干扰素产生。
Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.
作者信息
Gielen Vera, Sykes Annemarie, Zhu Jie, Chan Brian, Macintyre Jonathan, Regamey Nicolas, Kieninger Elisabeth, Gupta Atul, Shoemark Amelia, Bossley Cara, Davies Jane, Saglani Sejal, Walker Patrick, Nicholson Sandra E, Dalpke Alexander H, Kon Onn-Min, Bush Andrew, Johnston Sebastian L, Edwards Michael R
机构信息
Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom.
Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Centre for Respiratory Infection, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom.
出版信息
J Allergy Clin Immunol. 2015 Jul;136(1):177-188.e11. doi: 10.1016/j.jaci.2014.11.039. Epub 2015 Jan 25.
BACKGROUND
Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ 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.
背景
鼻病毒感染是哮喘急性加重的主要原因，哮喘患者中病毒诱导的IFN-α/β/λ不足在哮喘急性加重的发病机制中起重要作用。导致哮喘患者这种干扰素缺乏的机制尚不清楚。
目的
我们试图研究哮喘患者组织中细胞因子信号转导抑制因子（SOCS）1的表达及其在这些患者病毒诱导的干扰素诱导受损中的可能作用。
方法
我们在体外、支气管活检标本和小鼠中评估了SOCS1的mRNA和蛋白质水平。通过使用报告基因过表达和SOCS1缺陷小鼠的概念验证研究推断SOCS1的作用。通过支气管活检染色、突变型SOCS1构建体的过表达和共聚焦显微镜显示了SOCS1的核作用。SOCS1水平也与哮喘相关的临床结果相关。
结果
我们报告了哮喘急性加重相关细胞因子和体外鼻病毒感染可诱导支气管上皮细胞（BECs）中SOCS1的表达。我们发现体内支气管上皮中SOCS1增加且与哮喘严重程度相关。体外哮喘患者原代BECs中SOCS1表达也增加，且与干扰素缺乏和病毒复制增加有关。在原代人上皮细胞、小鼠肺巨噬细胞和SOCS1缺陷小鼠中，SOCS1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SOCS1的核转位，但不依赖于转录因子的蛋白酶体降解。哮喘患者BECs中核SOCS1水平也增加。
结论
我们描述了一种通过SOCS1的新核功能解释哮喘患者干扰素缺乏的新机制，并将SOCS1确定为哮喘急性加重的重要治疗靶点。
Zotero 插件