IL-17A Attenuates IFN-λ Expression by Inducing Suppressor of Cytokine Signaling Expression in Airway Epithelium
IL-17A Attenuates IFN-λ Expression by Inducing Suppressor of Cytokine Signaling Expression in Airway Epithelium
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DOI：
10.4049/jimmunol.1800147
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发表时间：
2018-10-15
影响因子：
4.4
通讯作者：
Suda, Takafumi
中科院分区：
文献类型：
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作者：
Niwa, Mitsuru;Fujisawa, Tomoyuki;Suda, Takafumi
IFN-λ是一种在上皮组织中表达的细胞因子，在抗病毒粘膜免疫应答中起核心作用。IFN-λ在气道中的表达在慢性气道疾病中受损（例如，哮喘、慢性阻塞性肺病），这使得患者易受病毒感染。IL-17 A与哮喘和慢性阻塞性肺病发病机制相关;然而，IL-17 A对IFN-λ表达的调节仍不清楚。本研究的目的是阐明IL-17 A介导的人气道上皮细胞中IFN-λ表达的调节机制。在这项研究中，我们已经表明，聚肌苷酸：聚胞苷酸（polyI：C）和甲型流感病毒（IAV）感染增加IFN-λ的表达在mRNA和蛋白质水平的正常人支气管上皮细胞的原代培养，而IL-17 A衰减polyI：C或IAV诱导的IFN-λ的表达。IFN-λ受体1敲除和JAK抑制剂ruxolitinib减弱了polyI：C诱导的IFN-λ表达，证实了正自分泌反馈环，IFN-λ受体-JAK-STAT途径，参与了IFN-λ表达。在Western印迹分析中，我们证明了polyI：C和IAV感染诱导正常人支气管上皮细胞中的STAT 1磷酸化，而IL-17 A抑制polyI：C或IAV介导的STAT 1磷酸化。此外，我们发现，与IL-17 A和polyI：C或IAV感染的共处理协同增加细胞因子信号转导抑制因子（SOCS）1和SOCS 3的表达。SOCS 1小干扰RNA和SOCS 3小干扰RNA通过恢复减弱的STAT 1磷酸化来否定IL-17 A在polyI：C诱导的IFN-λ表达中的抑制作用。总之，这些发现表明IL-17 A通过增强SOCS 1和SOCS 3表达来抑制人气道上皮细胞中的自分泌信号环，从而减弱病毒诱导的IFN-λ表达。
IFN-lambda is a cytokine expressed in epithelial tissues and plays a central role in antiviral mucosal immune response. The expression of IFN-lambda in the airway is impaired in chronic airway diseases (e.g., asthma, chronic obstructive pulmonary disease), which renders patients susceptible to viral infection. IL-17A is associated with asthma and chronic obstructive pulmonary disease pathogenesis; however, IL-17A regulation of IFN-lambda expression remains unclear. The aim of the current study is to clarify IL-17A-mediated regulatory mechanisms of IFN-lambda expression in human airway epithelial cells. In this study, we have shown that polyinosinic:polycytidylic acid (polyI:C) and influenza A virus (IAV) infection increased IFN-lambda expression at mRNA and protein levels in primary cultures of normal human bronchial epithelial cells, whereas IL-17A attenuated polyI:C-or IAV-induced IFN-lambda expression. IFN-lambda receptor 1 knockdown and a JAK inhibitor, ruxolitinib, attenuated polyI:C-induced IFN-lambda expression, confirming that a positive autocrine feedback loop, the IFN-lambda receptor-JAK-STAT pathway, was involved in IFN-lambda expression. In Western blotting analysis, we demonstrated that polyI:C and IAV infection induced STAT1 phosphorylation in normal human bronchial epithelial cells, whereas IL-17A suppressed polyI:C-or IAV-mediated STAT1 phosphorylation. Furthermore, we found that cotreatment with IL-17A and polyI:C or IAV infection synergistically increased suppressor of cytokine signaling (SOCS) 1 and SOCS3 expression. SOCS1 small interfering RNA and SOCS3 small interfering RNA negated the inhibitory effect of IL-17A in polyI:C-induced IFN-lambda expression by restoring attenuated STAT1 phosphorylation. Taken together, these findings indicate that IL-17A attenuates virus-induced IFN-lambda expression by enhancing SOCS1 and SOCS3 expression to inhibit autocrine signaling loops in human airway epithelial cells.