TGFβ1 Induces IL-6 and Inhibits IL-8 Release in Human Bronchial Epithelial Cells: The Role of Smad2/3
TGFβ1 Induces IL-6 and Inhibits IL-8 Release in Human Bronchial Epithelial Cells: The Role of Smad2/3
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DOI：
10.1002/jcp.22295
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发表时间：
2010-12-01
影响因子：
5.6
通讯作者：
Burgess, Janette K.
中科院分区：
文献类型：
--
作者：
Ge, Qi;Moir, Lyn M.;Burgess, Janette K.
人支气管上皮（HBE）细胞通过分泌细胞因子、趋化因子和生长因子（包括白细胞介素（IL）-6、IL-8和转化生长因子（TGF）β 1）促进哮喘气道炎症，所有这些在哮喘气道中升高。本研究检测了哮喘和非哮喘志愿者的原代HBE细胞中导致TGF β 1诱导IL-6和IL-8的信号通路。在存在或不存在信号传导抑制剂的情况下，用TGF β 1刺激HBE细胞。ELISA法检测IL-6、IL-8蛋白表达，实时荧光定量PCR法检测IL-8 mRNA表达，Western blot法检测细胞信号激酶活性。在哮喘和非哮喘细胞中，TGF β 1增加IL-6，但抑制IL-8的产生;然而，TGF在哮喘细胞中诱导显著更多的IL-6。JNK MAP激酶的抑制部分降低了两个细胞组中TGF β 1诱导的IL-6。TGF β 1诱导Smad 2磷酸化，阻断Smad 2/3可防止哮喘和非哮喘细胞中TGF β 1调节的IL-6增加和IL-8产生减少。抑制Smad 2/3也增加了哮喘细胞基础IL-8的释放，但在非哮喘细胞中不增加。使用CHIP分析，我们证明了激活的Smad 2结合到IL-6，但不是IL-8启动子区。我们的结论是Smad 2/3通路是HBE细胞中主要的TGF β 1信号通路，并且这在哮喘支气管上皮细胞中改变。了解哮喘气道中异常促炎细胞因子产生的机制将有助于开发控制气道炎症的替代方法。J.细胞。225：846-854，2010。(C)2010 Wiley-Liss，Inc.
Human bronchial epithelial (HBE) cells contribute to asthmatic airway inflammation by secreting cytokines, chemokines, and growth factors, including interleukin (IL)-6, IL-8 and transforming growth factor (TGF) beta 1, all of which are elevated in asthmatic airways. This study examines the signaling pathways leading to TGF beta 1 induced IL-6 and IL-8 in primary HBE cells from asthmatic and non-asthmatic volunteers. HBE cells were stimulated with TGF beta 1 in the presence or absence of signaling inhibitors. IL-6 and IL-8 protein and mRNA were measured by ELISA and real-time PCR respectively, and cell signaling kinases by Western blot. TGF beta 1 increased IL-6, but inhibited IL-8 production in both asthmatic and non-asthmatic cells; however, TGF induced significantly more IL-6 in asthmatic cells. Inhibition of JNK MAP kinase partially reduced TGF beta 1 induced IL-6 in both cell groups. TGF beta 1 induced Smad2 phosphorylation, and blockade of Smad2/3 prevented both the TGF beta 1 modulated IL-6 increase and the decrease in IL-8 production in asthmatic and non-asthmatic cells. Inhibition of Smad2/3 also increased basal IL-8 release in asthmatic cells but not in non-asthmatic cells. Using CHIP assays we demonstrated that activated Smad2 bound to the IL-6, but not the IL-8 promoter region. We conclude that the Smad2/3 pathway is the predominant TGF beta 1 signaling pathway in HBE cells, and this is altered in asthmatic bronchial epithelial cells. Understanding the mechanism of aberrant pro-inflammatory cytokine production in asthmatic airways will allow the development of alternative ways to control airway inflammation. J. Cell. Physiol. 225: 846-854, 2010. (C) 2010 Wiley-Liss, Inc.