Background

Bronchial fibroblasts are the main structural cells responsible for extracellular matrix production and turnover in lung tissue. They play a key role in airway remodelling in asthma through different cytokines including interleukin (IL-6).

Objective

To decipher IL-6 signalling in bronchial fibroblasts obtained from severe eosinophilic asthmatics compared to mild asthmatics and healthy controls.

Methods

Human bronchial fibroblasts were isolated from bronchial biopsies of mild and severe eosinophilic asthmatics and non-atopic healthy controls. IL-6 was assessed by qRT-PCR and ELISA. Phosphorylated STAT3, SHP2 and p38/MAPK were evaluated by Western blot. Chemical inhibitors for SHP2 and p38 were used. Fibroblast proliferation was evaluated by BrdU incorporation test.

Results

IL-6 release was significantly increased in fibroblasts from mild and severe asthmatics compared to healthy controls. Fibroblasts from severe asthmatics showed a reduced STAT3 activation compared to mild asthmatics and healthy controls. Constitutive activation of phosphatase SHP2 was found to negatively regulate IL-6 induced STAT3 phosphorylation in fibroblasts from severe asthmatics. This effect was accompanied by a decrease in fibroblast proliferation rate due to the activated p38/mitogen-activated protein kinase. SHP2 and p38/MAPK specific inhibitors (PHPS1 and SB212190) significantly induce a restoration of STAT3 phosphorylation, IL-6 target gene expression and cell proliferation.

Conclusion

These data show dysregulated IL-6 signalling in bronchial fibroblasts derived from severe eosinophilic asthmatic subjects involving the protein tyrosine phosphatase SHP2 and p38MAPK. Collectively, our data provides new insights into the mechanisms by which bronchial fibroblasts regulate airway remodelling in severe asthma.

中文翻译：

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在严重哮喘中，IL-6 / STAT3信号通路失衡向SHP2通路的转移导致增殖过程减少

背景

支气管成纤维细胞是负责肺组织中细胞外基质产生和更新的主要结构细胞。它们通过不同的细胞因子（包括白介素（IL-6））在哮喘的气道重塑中发挥关键作用。

客观的

与轻度哮喘和健康对照相比，从严重嗜酸性粒细胞性哮喘获得的支气管成纤维细胞中IL-6信号的解码。

方法

从轻度和重度嗜酸性粒细胞性哮喘患者和非特应性健康对照者的支气管活检组织中分离出人支气管成纤维细胞。通过qRT-PCR和ELISA评估IL-6。通过Western印迹评估磷酸化的STAT3，SHP2和p38 / MAPK。使用了SHP2和p38的化学抑制剂。通过BrdU掺入测试评价成纤维细胞增殖。

结果

与健康对照组相比，轻度和重度哮喘患者的成纤维细胞中IL-6的释放显着增加。与轻度哮喘患者和健康对照组相比，重度哮喘患者的成纤维细胞显示出STAT3激活降低。发现在严重哮喘患者的成纤维细胞中，磷酸酶SHP2的组成性活化可负调节IL-6诱导的STAT3磷酸化。由于活化的p38 /丝裂原活化的蛋白激酶，该作用伴随着成纤维细胞增殖速率的降低。SHP2和p38 / MAPK特异性抑制剂（PHPS1和SB212190）显着诱导STAT3磷酸化，IL-6靶基因表达和细胞增殖的恢复。

结论

这些数据显示，源自严重嗜酸性粒细胞哮喘受试者的支气管成纤维细胞中IL-6信号失调，涉及蛋白酪氨酸磷酸酶SHP2和p38MAPK。总体而言，我们的数据为支气管成纤维细胞调节严重哮喘中气道重塑的机制提供了新的见解。