Epidermal growth factor receptor signaling to Erk1/2 and STATs control the intensity of the epithelial inflammatory responses to rhinovirus infection
Epidermal growth factor receptor signaling to Erk1/2 and STATs control the intensity of the epithelial inflammatory responses to rhinovirus infection
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DOI：
10.1074/jbc.m710257200
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发表时间：
2008-04-11
影响因子：
4.8
通讯作者：
Bozinovski, Steven
中科院分区：
文献类型：
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作者：
Liu, Kenneth;Gualano, Rosa C.;Bozinovski, Steven
鼻病毒感染是导致哮喘和慢性阻塞性肺病等炎症性肺部疾病急性发作的最常见原因，它会引发类固醇难治性和异常强烈的中性粒细胞炎症，从而危及生命。在这些情况下，表皮生长因子受体 (EGFR) 表达与疾病严重程度和中性粒细胞浸润相关。然而，EGFR 信号传导在鼻病毒感染中的作用尚不清楚。我们测量了鼻病毒（RV16 血清型）感染的支气管上皮细胞 BEAS-2B 中中性粒细胞炎症白细胞介素 (IL)-8 和 ICAM-1 的关键决定因素。 RV16 感染刺激 IL-8 和 ICAM-1 表达，并通过 EGFR 水平的短暂上调进一步升高（2 倍）。通过定量实时 PCR 检测病毒 RNA 证实表达增强与病毒复制增加无关。 RV16 感染诱导 EGFR 配体（上皮调节蛋白、双调蛋白和肝素结合表皮生长因子），抑制负责配体脱落的金属蛋白酶可部分抑制这种反应。 EGFR 抑制剂 AG1478 将 IL-8 和 ICAM-1 表达完全阻断至基础水平，特异性 Erk1/2 抑制剂 U0126 也是如此。 p38 丝裂原激活蛋白激酶抑制剂 SB203580 阻断 IL-8 分泌，但不阻断 ICAM-1 表达，而 PI3K 抑制剂渥曼青霉素在这两种反应中均无效。激酶失活的 K721R EGFR 选择性地缺乏 STAT 信号传导，可逆转与 EGFR 过度表达相关的 RV16 反应。总之，RV16 感染迅速促进 EGFR 配体的诱导，并利用 EGFR 信号传导增加 IL-8 和 ICAM-1 水平。这些结果表明，靶向 EGFR 可能提供一种选择性疗法，抑制中性粒细胞驱动的炎症，而不损害由 TLR3 等病原体识别受体介导的基本抗病毒途径。
Rhinovirus infection is the most common cause of acute exacerbations of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease, where it provokes steroid refractory and abnormally intense neutrophilic inflammation that can be life threatening. Epidermal growth factor receptor (EGFR) expression correlates with disease severity and neutrophil infiltration in these conditions. However, the role of EGFR signaling in rhinovirus infection is unknown. We measured the key determinants of neutrophilic inflammation interleukin (IL)-8 and ICAM-1 in rhinovirus (RV16 serotype)- infected bronchial epithelial cells, BEAS-2B. RV16 infection stimulated IL-8 and ICAM-1 expression, which was further elevated (2-fold) by transient up-regulation of EGFR levels. Detection of viral RNA by quantitative real time PCR confirmed that enhanced expression was not associated with increased viral replication. EGFR ligands (epiregulin, amphiregulin, and heparin-binding epidermal growth factor) were induced by RV16 infection, and inhibition of metalloproteases responsible for ligand shedding partially suppressed this response. The EGFR inhibitor AG1478, completely blocked IL-8 and ICAM-1 expression to basal levels, as did the specific Erk1/2 inhibitor U0126. The p38 mitogen-activated protein kinase inhibitor SB203580 blocked IL-8 secretion but not ICAM-1 expression, whereas the PI3K inhibitor wortmannin was ineffective in both responses. Kinase inactive K721R EGFR, which is selectively deficient in STAT signaling, reversed RV16 responses associated with EGFR overexpression. In conclusion, RV16 infection rapidly promotes induction of EGFR ligands and utilizes EGFR signaling to increase IL-8 and ICAM-1 levels. These results suggest that targeting EGFR may provide a selective therapy that dampens neutrophil-driven inflammation without compromising essential antiviral pathways mediated by pathogen recognition receptors such as TLR3.