重症嗜酸粒细胞性哮喘患者中上皮细胞因子信号通路抑制因子1降低
2016/12/27
背景：重症哮喘是临床未满足需求的疾病。尽管给予大剂量吸入激素治疗，许多未控制的哮喘患者仍持续存在气道嗜酸粒细胞性炎症。细胞因子信号通路抑制因子（Suppressors of cytokine signaling, SOCS）是一类分子家族，通过抑制Janus 激酶信号转导与转录通路活化因子（Janus kinase–signal transducers and activators of transcription），参与到细胞因子的调节。。我们检测哮喘患者气道中SOCS的表达水平，并且探索是否与持续性嗜酸性粒细胞增多相关。
方法：该研究纳入健康受试者、轻度/中度哮喘受试者和重症哮喘受试者。全基因表达谱、定量PCR和免疫组化分析用来检测支气管活检组织中SOCS1、SOCS2、SOCS3的表达。在体外，使用支气管上皮细胞检测SOCS1在调节白介素-13（interleukin (IL)-13）信号通路中扮演的角色。
结果：与轻度或中度哮喘受试者比较，重症哮喘患者气道中SOCS1基因表达明显减少，并与气道嗜酸粒细胞增多以及其它Th2型细胞因子呈负相关。免疫组化显示SOCS1主要定位于支气管上皮。在支气管上皮细胞中，SOCS1的过度表达抑制了IL-13介导的趋化因子配体26（CCL-26）（嗜酸性粒细胞趋化因子-3，eotaxin-3）mRNA的表达。
结论：重症哮喘患者存在着持续性气道嗜酸性粒细胞增多以及Th2型炎症，其SOCS1在气道上皮中表达降低。SOCS1抑制上皮细胞IL-13信号通路，它对重症哮喘患者调节Th2驱动的嗜酸性粒细胞增多，发挥着关键作用。
Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic
asthmaEmma Doran, David F. Choy, Aarti Shikotra, Claire A. Butler,Declan M. O’Rourke, James A. Johnston, Adrien Kissenpfennig,Peter Bradding, Joseph R. Arron, Liam G. HeaneyEur Respir J.2016 Sep;48(3):715-25. doi: 10.1183/13993003.00400-2015. Epub 2016 Jun 23.
BACKGROUND：Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase–signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.
METHOD：Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitro.
RESULTS：SOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.
CONCLUSIONS：Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.
方法：该研究纳入健康受试者、轻度/中度哮喘受试者和重症哮喘受试者。全基因表达谱、定量PCR和免疫组化分析用来检测支气管活检组织中SOCS1、SOCS2、SOCS3的表达。在体外，使用支气管上皮细胞检测SOCS1在调节白介素-13（interleukin (IL)-13）信号通路中扮演的角色。
结果：与轻度或中度哮喘受试者比较，重症哮喘患者气道中SOCS1基因表达明显减少，并与气道嗜酸粒细胞增多以及其它Th2型细胞因子呈负相关。免疫组化显示SOCS1主要定位于支气管上皮。在支气管上皮细胞中，SOCS1的过度表达抑制了IL-13介导的趋化因子配体26（CCL-26）（嗜酸性粒细胞趋化因子-3，eotaxin-3）mRNA的表达。
结论：重症哮喘患者存在着持续性气道嗜酸性粒细胞增多以及Th2型炎症，其SOCS1在气道上皮中表达降低。SOCS1抑制上皮细胞IL-13信号通路，它对重症哮喘患者调节Th2驱动的嗜酸性粒细胞增多，发挥着关键作用。
(陈如月 张红萍 王刚 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Liam G. HeaneyEur Respir J.2016 Sep;48(3):715-25. doi: 10.1183/13993003.00400-2015. Epub 2016 Jun 23.）
（Liam G. HeaneyEur Respir J.2016 Sep;48(3):715-25. doi: 10.1183/13993003.00400-2015. Epub 2016 Jun 23.）
Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic
asthmaEmma Doran, David F. Choy, Aarti Shikotra, Claire A. Butler,Declan M. O’Rourke, James A. Johnston, Adrien Kissenpfennig,Peter Bradding, Joseph R. Arron, Liam G. HeaneyEur Respir J.2016 Sep;48(3):715-25. doi: 10.1183/13993003.00400-2015. Epub 2016 Jun 23.
BACKGROUND：Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase–signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.
METHOD：Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitro.
RESULTS：SOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.
CONCLUSIONS：Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.
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