Liu Kenneth, Gualano Rosa C, Hibbs Margaret L, Anderson Gary P, Bozinovski Steven
Departments of Pharmacology and Medicine, University of Melbourne, Melbourne, Victoria 3010, Australia.
J Biol Chem. 2008 Apr 11;283(15):9977-85. doi: 10.1074/jbc.M710257200. Epub 2008 Feb 13.
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.
鼻病毒感染是炎症性肺部疾病急性加重的最常见原因，如哮喘和慢性阻塞性肺疾病，它会引发类固醇难治性且异常强烈的中性粒细胞炎症，这种炎症可能危及生命。在这些病症中，表皮生长因子受体（EGFR）的表达与疾病严重程度及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。我们在鼻病毒（RV16血清型）感染的支气管上皮细胞BEAS-2B中测量了中性粒细胞炎症的关键决定因素白细胞介素（IL）-8和细胞间黏附分子-1（ICAM-1）。RV16感染刺激了IL-8和ICAM-1的表达，EGFR水平的短暂上调使其进一步升高（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感染诱导了EGFR配体（表皮调节素、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的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丝裂原活化蛋白激酶抑制剂SB203580阻断了IL-8的分泌，但未阻断ICAM-1的表达，而PI3K抑制剂渥曼青霉素对这两种反应均无效。激酶失活的K721R EGFR选择性缺乏STAT信号传导，可逆转与EGFR过表达相关的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的水平。这些结果表明，靶向EGFR可能提供一种选择性疗法，可减轻中性粒细胞驱动的炎症，而不会损害由病原体识别受体（如TLR3）介导的基本抗病毒途径。
