Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma.
Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma.
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DOI：
10.1093/hmg/ddx053
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发表时间：
2017-04-15
影响因子：
3.5
通讯作者：
Chilvers ER
中科院分区：
文献类型：
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作者：
Farahi N;Paige E;Balla J;Prudence E;Ferreira RC;Southwood M;Appleby SL;Bakke P;Gulsvik A;Litonjua AA;Sparrow D;Silverman EK;Cho MH;Danesh J;Paul DS;Freitag DF;Chilvers ER
白细胞介素-6受体（IL-6 R）基因中的Asp 358 Ala变体与哮喘、自身免疫性和心血管疾病有关，但其在其他呼吸系统疾病如慢性阻塞性肺疾病（COPD）中的作用尚未研究。本研究的目的是评估Asp 358 Ala与COPD或哮喘风险之间是否存在关联，并探讨Asp 358 Ala变体在中性粒细胞释放sIL-6 R中的作用及其在肺部的促炎作用。我们使用来自英国生物样本库和ECLIPSE COPD队列的数据进行逻辑回归。采用来自另外3个COPD队列（总计7，519例病例和总计35，653例对照）的汇总数据对结果进行荟萃分析，结果显示Asp 358 Ala与COPD之间无相关性（OR = 1.02 [95% CI：0.96，1.07]）。来自英国生物样本库的数据显示Asp 358 Ala变异体与特应性哮喘之间存在正相关性（OR = 1.07 [1.01，1.13]）。在一系列使用37名参与者血液样本的体外研究中，我们发现Asp 358 Ala次要等位基因携带者的中性粒细胞释放的sIL-6 R高于非携带者。用纯合子携带者血清培养的人肺动脉内皮细胞显示次要等位基因携带者MCP-1释放增加，加入托珠单抗后差异消除。总之，有证据表明，中性粒细胞可能是一个重要的来源，sIL-6 R在肺部，Asp 358 Ala变异体可能有促炎作用的肺细胞。然而，我们无法确定Asp 358 Ala与COPD之间相关性的证据。
The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.