Th-17 regulatory cytokines inhibit corticosteroid induced airway structural cells apoptosis.
Th-17 regulatory cytokines inhibit corticosteroid induced airway structural cells apoptosis.
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DOI：
10.1186/s12931-015-0307-2
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发表时间：
2016-01-16
影响因子：
5.8
通讯作者：
Al-Muhsen S
中科院分区：
文献类型：
--
作者：
Halwani R;Sultana A;Al-Kufaidy R;Jamhawi A;Vazquez-Tello A;Al-Muhsen S
虽然皮质类固醇是一种有效的抗炎药物，被广泛用于控制哮喘，但严重的哮喘患者仍可产生类固醇耐药性。在特发性肺纤维化(IPF)期间，呼吸道成纤维细胞对类固醇具有相当的抵抗力，哮喘肺的纤维化并不总是得到控制。在哮喘患者肺组织中升高的TH-17调节细胞因子被证明能提高各种类型细胞的存活率。STAT因子是这种抗细胞凋亡功能的核心。然而，目前尚不清楚这些细胞因子是否与哮喘患者的类固醇低反应性有关。因此，在本研究中，我们研究了Th-17调节细胞因子，特别是IL-21、IL-22和IL-23，对地塞米松诱导的呼吸道结构细胞凋亡的保护作用。原代培养的人成纤维细胞、ASM细胞和肺内皮细胞系在地塞米松孵育前分别加入IL-21、IL-22和IL-23细胞因子，通过流式细胞仪检测细胞膜联蛋白-V(Annexin-V)的表达来检测细胞的凋亡水平。结果表明，Th-17调节细胞因子可有效抑制成纤维细胞和血管内皮细胞的凋亡，但不能抑制ASM细胞的凋亡。在这些细胞因子作用下，成纤维细胞和内皮细胞中的STAT3磷酸化水平也被上调。有趣的是，抑制STAT3的磷酸化可以消除IL-21、IL-22和IL-23对成纤维细胞和内皮细胞的抗凋亡作用。这一数据表明，Th-17调节细胞因子可能在哮喘、IPF以及其他导致纤维化加重的慢性肺炎性疾病中调节成纤维细胞的存活起关键作用。因此，这篇论文的发现可能为更广泛地研究这些调节性细胞因子在各种慢性炎症性疾病的纤维化发展中的作用铺平道路。
Although corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. Th-17 regulatory cytokine which are elevated in lung tissues of asthmatics were shown to enhance the survival of various types of cells. STAT factors are central to this anti-apoptotic function. However, it is not yet clear whether these cytokines contribute to steroid hypo-responsiveness in asthma. Therefore, in this study, we investigated the ability of Th-17 regulatory cytokines, specifically IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis. Primary human fibroblasts, ASM cells, and lung endothelial cells line were treated with IL-21, IL-22, and IL-23 cytokines before incubation with dexamethasone and the level of apoptosis was determined by measuring cellular Annexin-V using Flow cytometry. Our data indicated that treatment with Th-17 regulatory cytokines was effective in inhibiting induced apoptosis for both fibroblasts and endothelial cells but not ASM cells. STAT3 phosphorylation levels were also upregulated in fibroblasts and endothelial upon treatment with these cytokines. Interestingly, inhibiting STAT3 phosphorylation abrogated IL-21, IL-22, and IL-23 anti-apoptotic effect on fibroblasts and endothelial cells. This data suggest that Th-17 regulatory cytokines may play a critical role in regulating the survival of fibroblasts during asthma, IPF as well as other chronic lung inflammatory diseases leading to enhanced fibrosis. Accordingly, findings of this paper may pave the way for more extensive research on the role of these regulatory cytokines in fibrosis development in various chronic inflammatory diseases.