白细胞介素-4受体通过抑制白细胞介素-4/信号转导子和转录激活子6信号通路来抑制支气管哮喘中的气道炎症。

IL-4R suppresses airway inflammation in bronchial asthma by inhibiting the IL-4/STAT6 pathway.

作者信息

Liu Ying, Zhang Hui, Ni Ran, Jia Wen-Qing, Wang Yuan-Yuan

机构信息

Department of Respiration Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China.

出版信息

Pulm Pharmacol Ther. 2017 Apr;43:32-38. doi: 10.1016/j.pupt.2017.01.006. Epub 2017 Jan 16.

DOI:10.1016/j.pupt.2017.01.006

PMID:28093225

Abstract

OBJECTIVE

This study aims to explore the mechanisms of how IL-4R suppresses airway inflammation in bronchial asthma by inhibiting the IL-4/STAT6 pathway.

METHODS

A total of 27 BALB/c male mice were selected and divided into control, asthma and IL-4R groups. Ovalbumin-induced mouse asthma model was established. Maximal pulmonary resistance was recorded. Hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining were conducted to observe the pathological changes in lung tissue. Optical microscope was used to detect numbers of total cells, mastocytes, eosinophils (EOS), neutrophils, and lymphocytes. Enzyme-linked immunosorbent assay (ELISA) was adopted for the levels of immunoglobulin (IgE), IL-4, IL-5, IL-13 and interferon (IFN)-γ, flow cytometry for the percentages of IL-4 CD4, IFN-γ CD4 and IFN-γ/IL-4 in total thymus-derived (T) cells, qRT-PCR for the mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, suppressor of cytokine signaling (SOCS), inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1, and Western blotting for the protein expressions of STAT6 and pSTAT6.

RESULTS

Compared with the control group, the asthma group had irregular tissue structure and severe inflammation, increases in maximal pulmonary resistance, numbers of total cells, EOS, neutrophils, and lymphocytes, levels of IgE, IL-4, IL-5 and IL-13, percentages of IFN-γ CD4 and IFN-γ/IL-4 in total T cells, mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, SOCS, iNOS and VCAM-1, and protein expressions of STAT6 and pSTAT6, but decreases in IFN-γ level and percentage of IL-4 CD4 in total T cells. Compared with the asthma group, the IL-4R group had relatively regular tissue structure and light inflammation, declined maximal RL, numbers of total cells, EOS, neutrophils, and lymphocytes, contents of IgE, IL-4, IL-5 and IL-13, percentages of IFN-γ CD4 and IFN-γ/IL-4 in total T cells, mRNA expressions of IL-4, IL-5, IL-13, STAT6, pSTAT6, SOCS, iNOS and VCAM-1, and protein expressions of STAT6 and pSTAT6, but elevated IFN-γ content and percentage of IL-4 CD4 in total T cells.

CONCLUSION

Our results demonstrate that IL-4R can suppress airway inflammation in bronchial asthma by inhibited the IL-4/STAT6 pathway, which may provide a new therapeutic approach for the treatment of bronchial asthma.

摘要

目的

本研究旨在探讨白细胞介素4受体（IL-4R）通过抑制IL-4/信号转导及转录激活因子6（STAT6）通路来抑制支气管哮喘气道炎症的机制。

方法

选取27只雄性BALB/c小鼠，分为对照组、哮喘组和IL-4R组。建立卵清蛋白诱导的小鼠哮喘模型。记录最大肺阻力。进行苏木精-伊红（HE）染色和过碘酸希夫（PAS）染色以观察肺组织的病理变化。用光学显微镜检测总细胞、肥大细胞、嗜酸性粒细胞（EOS）、中性粒细胞和淋巴细胞的数量。采用酶联免疫吸附测定（ELISA）法检测免疫球蛋白（IgE）、IL-4、IL-5、IL-13和干扰素（IFN）-γ的水平，用流式细胞术检测总胸腺来源（T）细胞中IL-4 CD4、IFN-γ CD4和IFN-γ/IL-4的百分比，用实时定量聚合酶链反应（qRT-PCR）检测IL-4、IL-5、IL-13、STAT6、磷酸化STAT6（pSTAT6）、细胞因子信号抑制因子（SOCS）、诱导型一氧化氮合酶（iNOS）和血管细胞黏附分子（VCAM）-1的mRNA表达，并用蛋白质印迹法检测STAT6和pSTAT6的蛋白表达。

结果

与对照组相比，哮喘组组织结构不规则且炎症严重，最大肺阻力增加，总细胞、EOS、中性粒细胞和淋巴细胞数量增加，IgE、IL-4、IL-5和IL-13水平升高，总T细胞中IFN-γ CD4和IFN-γ/IL-4的百分比增加，IL-4、IL-5、IL-13、STAT6、pSTAT6、SOCS、iNOS和VCAM-1的mRNA表达以及STAT6和pSTAT6的蛋白表达增加，但总T细胞中IFN-γ水平和IL-4 CD4百分比降低。与哮喘组相比，IL-4R组组织结构相对规则且炎症较轻，最大肺阻力降低，总细胞、EOS、中性粒细胞和淋巴细胞数量减少，IgE、IL-4、IL-5和IL-13含量降低，总T细胞中IFN-γ CD4和IFN-γ/IL-4的百分比降低，IL-4、IL-5、IL-13、STAT6、pSTAT6、SOCS、iNOS和VCAM-1的mRNA表达以及STAT6和pSTAT6的蛋白表达降低，但总T细胞中IFN-γ含量和IL-4 CD4百分比升高。