Viral Stimuli Trigger Exaggerated Thymic Stromal Lymphopoietin Expression by Chronic Obstructive Pulmonary Disease Epithelium: Role of Endosomal TLR3 and Cytosolic RIG-I-Like Helicases
Viral Stimuli Trigger Exaggerated Thymic Stromal Lymphopoietin Expression by Chronic Obstructive Pulmonary Disease Epithelium: Role of Endosomal TLR3 and Cytosolic RIG-I-Like Helicases
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DOI：
10.1159/000329131
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Uller, Lena
中科院分区：
文献类型：
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作者：
Calven, Jenny;Yudina, Yulyana;Uller, Lena
背景：鼻病毒（RV）诱导的慢性阻塞性肺疾病（COPD）急性加重表现出TH 2样炎症。我们假设RV感染的支气管上皮细胞（BEC）过度产生TH 2转换中枢细胞因子，胸腺基质淋巴细胞生成素（TSLP）在COPD。研究方法：将来自健康（HBEC）和来自COPD供体（COPD-BEC）的原代BEC在12孔板中生长，用RV 16（0.5-5 MOI）感染或用toll样受体（TLR）3（dsRNA，0.1-10 μ g/ml）或RIG-1样解旋酶（dsRNA-LyoVec，0.1-10 μ g/ml）的激动剂刺激。测定细胞因子mRNA和蛋白（RTqPCR; ELISA）。结果：与HBEC相比，dsRNA剂量依赖性地诱导COPD-BEC中TSLP、CXCL 8和TNF-α的细胞因子基因过量产生。这一点通过RV 16感染得到证实。IFN-β诱导在COPD-BEC和HBEC之间没有差异。氯喹剂量依赖性地抑制内体TLR 3抑制dsRNA诱导的TSLP产生，并减少CXCL 8、TNF-α和IFN-α的产生。用dsRNA-LyoVec刺激胞质病毒传感器（RIG-I样解旋酶）增加了CXCL 8、TNF-α和IFN-β的产生，但不增加TSLP的产生。结论：内体TLR 3的刺激，dsRNA或RV 16，诱导TSLP在COPD-BEC的过度生产。dsRNA和RV诱导的TNF-α和CXCL 8的过度产生涉及内体TLR 3和胞质RIG-I样解旋酶，并且在COPD-BEC中IFN-β的产生也是如此。RV 16和dsRNA诱导的上皮TSLP可能有助于COPD恶化和发展的致病作用。
Background: Rhinovirus (RV)-induced chronic obstructive pulmonary disease (COPD) exacerbations exhibit TH2-like inflammation. We hypothesized that RV-infected bronchial epithelial cells (BEC) overproduce TH2-switching hub cytokine, thymic stromal lymphopoietin (TSLP) in COPD. Methods: Primary BEC from healthy (HBEC) and from COPD donors (COPD-BEC) were grown in 12-well plates, infected with RV16 (0.5-5 MOI) or stimulated with agonists for either toll-like receptor (TLR) 3 (dsRNA, 0.1-10 mu g/ml) or RIG-I-like helicases (dsRNA-LyoVec, 0.1-10 mu g/ml). Cytokine mRNA and protein were determined (RTqPCR; ELISA). Results: dsRNA dose-dependently evoked cytokine gene overproduction of TSLP, CXCL8 and TNF-alpha in COPD-BEC compared to HBEC. This was confirmed using RV16 infection. IFN-beta induction did not differ between COPD-BEC and HBEC. Endosomal TLR3 inhibition by chloroquine dose-dependently inhibited dsRNA-induced TSLP generation and reduced generation of CXCL8, TNF-alpha, and IFN-alpha. Stimulation of cytosolic viral sensors (RIG-I-like helicases) with dsRNA-LyoVec increased production of CXCL8, TNF-alpha, and IFN-beta, but not TSLP. Conclusions: Endosomal TLR3-stimulation, by dsRNA or RV16, induces overproduction of TSLP in COPD-BEC. dsRNA-and RV-induced overproduction of TNF-alpha and CXCL8 involves endosomal TLR3 and cytosolic RIG-I-like helicases and so does the generation of IFN-beta in COPD-BEC. RV16 and dsRNA-induced epithelial TSLP may contribute to pathogenic effects at exacerbations and development of COPD.