The IκB kinase is a key factor in triggering influenza A virus-induced inflammatory cytokine production in airway epithelial cells
The IκB kinase is a key factor in triggering influenza A virus-induced inflammatory cytokine production in airway epithelial cells
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DOI：
10.1074/jbc.m413726200
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发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Santoro, MG
中科院分区：
文献类型：
--
作者：
Bernasconi, D;Amici, C;Santoro, MG
甲型流感病毒继续在全世界构成严重威胁，造成大规模流行病和大流行，每年造成数千人死亡。由于气道上皮细胞过度产生促炎细胞因子而导致的过度炎症被认为是疾病发病机制中的重要因素。我们在此报道甲型流感病毒诱导人气道上皮A549细胞I κ B激酶（IKK）活性，导致炎症反应的关键调节因子核因子-κ B（NF-κ B）持续活化。尽管肺上皮细胞对流感病毒感染引起的IKK/NF-κ B通路的刺激高度敏感，但NF-κ B在几种允许病毒的非肺细胞中未被激活，表明细胞特异性应答。此外，NF-κ B不是病毒复制所必需的，但触发了感染肺细胞中促炎细胞因子的表达，并直接导致高水平白细胞介素-8的产生，白细胞介素-8是一种与流感诱导的炎症和气道病理学相关的趋化因子。我们还报告了9-脱氧-Delta（9），Delta（12）-13，14-二氢-前列腺素D-2，一种在临床前研究中对流感具有治疗功效的环戊烯酮前列腺素类化合物，是流感病毒诱导的IKK活性和人肺细胞产生白细胞介素-8的强效抑制剂。结果确定IKK是触发流感病毒诱导的肺上皮炎症反应的重要因素，提示了治疗流感的新方法。
Influenza A viruses continue to represent a severe threat worldwide, causing large epidemics and pandemics responsible for thousands of deaths every year. Excessive inflammation due to overabundant production of proinflammatory cytokines by airway epithelial cells is considered an important factor in disease pathogenesis. Here we report that influenza A virus induced I kappa B kinase (IKK) activity in human airway epithelial A549 cells, resulting in persistent activation of nuclear factor-kappa B (NF-kappa B), a critical regulator of the inflammatory response. Although lung epithelial cells are highly sensitive to stimulation of the IKK/NF-kappa B pathway by influenza virus infection, NF-kappa B was not activated in several non-pulmonary cells permissive to the virus, indicating a cell-specific response. Moreover, NF-kappa B was not essential for virus replication but triggered the expression of proinflammatory cytokines in infected lung cells and was directly responsible for production of high levels of interleukin-8, a chemokine associated with influenza-induced inflammation and airway pathology. We also report that 9-deoxy-Delta(9), Delta(12)-13,14-dihydro-prostaglandin D-2, a cyclopentenone prostanoid with therapeutic efficacy against influenza in preclinical studies, was a powerful inhibitor of influenza virus-induced IKK activity and interleukin-8 production by human pulmonary cells. The results identify IKK as an important factor in triggering influenza virus-induced inflammatory reactions in pulmonary epithelium, suggesting novel therapeutic approaches in the treatment of influenza.