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白细胞介素-17F 通过 TAK1-NFκB 通路在气道平滑肌细胞中诱导白细胞介素-6 的产生。

IL-17F induces IL-6 via TAK1-NFκB pathway in airway smooth muscle cells.

机构信息

Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Respiratory Disease Center, Showa University Northern Yokohama Hospital, Kanagawa, Japan.

出版信息

Immun Inflamm Dis. 2017 Jun;5(2):124-131. doi: 10.1002/iid3.149. Epub 2017 Mar 3.

Abstract

INTRODUCTION

Interleukin (IL)-17F plays a critical role in the pathophysiology of asthma. However, the precise role of IL-17F in airway smooth muscle cells (ASMCs) and its regulatory mechanisms remain to be defined. Therefore, we sought to investigate the expression of IL-6 by IL-17F and the involvement of transforming growth factor β-activated kinase 1 (TAK1) and nuclear factor (NF)-κB by in ASMCs.

METHODS

ASMCs were cultured in the presence or absence of IL-17F. The expression of IL-6 gene and protein was analyzed using real-time PCR and ELISA, and the activation of TAK1 and NF-κB was detected by Western blotting. The effect of TAK1 inhibitor 5Z-7-oxozeaenol and NF-κB inhibitor BAY 11-7082 on the expression of IL-6 was investigated. Finally, the short interfering RNAs (siRNAs) targeting TAK1 and a subunit of NF-κB, p65 were transfected into ASMCs.

RESULTS

The expression of IL-6 gene and protein was significantly induced by IL-17F. IL-17F activated TAK1 and NF-κB in ASMCs. Transfection of siRNAs targeting TAK1 abolished IL-17F-induced phosphorylation of p65. Both 5Z-7-oxozeaenol and BAY 11-7082 significantly inhibited IL-17F-induced IL-6 production in a dose-dependent manner. Similarly, transfection of the cells with siRNAs targeting TAK1 and p65 inhibited the expression of IL-6.

CONCLUSIONS

Collectively, these results provided evidence supporting the potential importance of the Th17-ASMCs crosstalk via the IL-17F-IL-6 axis in airway inflammation and as a candidate pharmacological target for airway inflammatory diseases such as asthma.

摘要

简介

白细胞介素(IL)-17F 在哮喘的病理生理学中起着关键作用。然而,IL-17F 在气道平滑肌细胞(ASMCs)中的确切作用及其调节机制仍有待确定。因此,我们试图研究 IL-17F 对 IL-6 的表达的影响,以及转化生长因子β激活激酶 1(TAK1)和核因子(NF)-κB 在 ASMCs 中的作用。

方法

在存在或不存在 IL-17F 的情况下培养 ASMCs。使用实时 PCR 和 ELISA 分析 IL-6 基因和蛋白的表达,并通过 Western blot 检测 TAK1 和 NF-κB 的激活。研究了 TAK1 抑制剂 5Z-7-氧杂氮杂环庚烯和 NF-κB 抑制剂 BAY 11-7082 对 IL-6 表达的影响。最后,将靶向 TAK1 和 NF-κB 的 p65 亚单位的 siRNA 转染到 ASMCs 中。

结果

IL-17F 显著诱导 IL-6 基因和蛋白的表达。IL-17F 在 ASMCs 中激活 TAK1 和 NF-κB。靶向 TAK1 的 siRNA 的转染消除了 IL-17F 诱导的 p65 磷酸化。5Z-7-氧杂氮杂环庚烯和 BAY 11-7082 均以剂量依赖性方式显著抑制 IL-17F 诱导的 IL-6 产生。同样,转染靶向 TAK1 和 p65 的 siRNA 抑制了 IL-6 的表达。

结论

综上所述,这些结果为 Th17-ASMCs 相互作用通过 IL-17F-IL-6 轴在气道炎症中的潜在重要性提供了证据,并为哮喘等气道炎症性疾病提供了候选的药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e48/5418132/61d39e7a052b/IID3-5-124-g002.jpg

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