IL-17 markedly up-regulates β-defensin-2 expression in human airway epithelium via JAK and NF-κB signaling pathways
IL-17 markedly up-regulates β-defensin-2 expression in human airway epithelium via JAK and NF-κB signaling pathways
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DOI：
10.4049/jimmunol.173.5.3482
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发表时间：
2004-09-01
影响因子：
4.4
通讯作者：
Wu, R
中科院分区：
文献类型：
--
作者：
Kao, CY;Chen, Y;Wu, R
使用微阵列基因表达分析，我们首先观察到在IL-17处理的原代人气道上皮细胞中人β-防御素-2（hBD-2）信息的显著升高。将这种刺激与一组细胞因子（IL-1 α、1 β、2-13和15-18; IFN-γ; GM-CSF;和TNF-α）的进一步比较表明，IL-17是诱导hBD-2信息的最有效的细胞因子（>75倍）。IL-17诱导的hBD-2的刺激是时间和剂量依赖性的，并且这种刺激也发生在蛋白水平上。进一步的研究表明，hBD-2刺激被IL-17 R特异性Ab减弱，但不被IL-1 R拮抗剂或中和性抗IL-6 Ab减弱。这表明IL-17 R介导的信号通路，而不是IL-17诱导的IL-1 α和/或IL-6自分泌/旁分泌环。hBD-2刺激对JAK通路的抑制敏感，对影响NF-κ B易位及其p65 NF-κ B亚基的DNA结合活性的抑制剂敏感。用hBD-2启动子-荧光素酶报告基因表达构建体瞬时转染气道上皮细胞表明，IL-17刺激启动子-报告基因活性，提示hBD-2诱导的转录机制。这些结果支持IL-17 R介导的信号通路，涉及JAK和NF-κ B在气道上皮中hBD-2基因表达的转录刺激。由于IL-17已在许多气道疾病，特别是与微生物感染相关的疾病中被鉴定，因此这些发现为IL-17如何在先天免疫和适应性免疫之间发挥重要作用提供了新的见解，从而在气道上皮内局部对抗感染。
Using microarray gene expression analysis, we first observed a profound elevation of human beta-defensin-2 (hBD-2) message in IL-17-treated primary human airway epithelial cells. Further comparison of this stimulation with a panel of cytokines (IL-1alpha, 1beta, 2-13, and 15-18; IFN-gamma; GM-CSF; and TNF-alpha) demonstrated that IL-17 was the most potent cytokine to induce hBD-2 message (>75-fold). IL-17-induced stimulation of hBD-2 was time and dose dependent, and this stimulation also occurred at the protein level. Further studies demonstrated that hBD-2 stimulation was attenuated by IL-17R-specific Ab, but not by IL-IR antagonist or the neutralizing anti-IL-6 Ab. This suggests an IL-17R-mediated signaling pathway rather than an IL-17-induced IL-1alphabeta and/or IL-6 autocrine/paracrine loop. hBD-2 stimulation was sensitive to the inhibition of the JAK pathway, and to the inhibitors that affect NF-kappaB translocation and the DNA-binding activity of its p65 NF-kappaB subunit. Transient transfection of airway epithelial cells with an hBD-2 promoter-luciferase reporter gene expression construct demonstrated that IL-17 stimulated promoter-reporter gene activity, suggesting a transcriptional mechanism for hBD-2 induction. These results support an IL-17R-mediated signaling pathway involving JAK and NF-kappaB in the transcriptional stimulation of hBD-2 gene expression in airway epithelium. Because IL-17 has been identified in a number of airway diseases, especially diseases related to microbial infection, these findings provide a new insight into how IL-17 may play an important link between innate and adaptive immunity, thereby combating infection locally within the airway epithelium.