Release of macrophage migration inhibitory factor and CXCL8/interleukin-8 from lung epithelial cells rendered necrotic by influenza A virus infection
Release of macrophage migration inhibitory factor and CXCL8/interleukin-8 from lung epithelial cells rendered necrotic by influenza A virus infection
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DOI：
10.1128/jvi.76.18.9298-9306.2002
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发表时间：
2002-09-01
影响因子：
5.4
通讯作者：
Bacher, M
中科院分区：
文献类型：
--
作者：
Arndt, U;Wennemuth, G;Bacher, M
支气管上皮细胞是甲型流感病毒感染的主要靶细胞。这些细胞产生哪些信号来启动免疫反应仍有待澄清。在趋化因子中，原代肺上皮细胞的病毒感染仅触发CXCL 8/白细胞介素-8（IL-8）的释放，这与我们先前的观察形成对比，即甲型流感病毒诱导单核细胞中单核白细胞吸引趋化因子的表达，甚至抑制嗜中性粒细胞吸引趋化因子的产生。因此，我们推测，呼吸道上皮细胞释放主要吸引嗜中性粒细胞的CXCL 8/IL-8可能是有利的，因为嗜中性粒细胞迅速清除坏死碎片，并且是抵抗细菌双重感染的第一道防线。我们发现甲型流感病毒感染导致肺上皮细胞坏死也支持了这一概念。这与先前的研究形成鲜明对比，在先前的研究中，甲型流感病毒感染诱导了来自肺以外来源的单核细胞和上皮细胞的凋亡。因此，细胞类型而不是病毒决定了将遵循哪种死亡途径。除了释放CXCL 8/IL-8外，我们还从病毒感染的肺细胞中获得了巨噬细胞迁移抑制因子（MIF）的大量释放。然而，尽管CXCL 8/IL-8的分泌伴随着诱导的基因激活，但在感染过程中MIF的转录速率保持不变，并且病毒诱导的MIF释放主要是从细胞内储存的释放，这表明MIF在细胞死亡后被动释放。尽管病毒诱导坏死，被动释放的MIF仍然具有生物活性。考虑到MIF对不同白细胞亚群的明确免疫刺激作用，在人类甲型流感病毒感染的急性期，MIF水平的提高很可能有助于宿主免疫应答。
Bronchiolar epithelial cells are the prime targets for influenza A virus infection. It still remains to be clarified which signals are generated from these cells to initiate an immune response. Among chemokines, viral infection of primary lung epithelial cells triggered exclusively the release of CXCL8/interleukin-8 (IL-8), which contrasts with our previous observation that influenza A virus induced in monocytes the expression of mononuclear-leukocyte-attracting chemokines and even suppressed the production of neutrophil-attracting chemokines. Therefore, we speculated that it may be advantageous for respiratory epithelial cells to release primarily neutrophil-attracting CXCL8/IL-8 since neutrophils rapidly remove necrotic debris and are the first line of defense against bacterial superinfections. This concept has also been supported by our finding that influenza A virus infection led to necrosis of lung epithelial cells. This is in striking contrast to previous studies where influenza A virus infection induced apoptosis in monocytes and epithelial cells from origins other than the lung. Thus, the cell type instead of the virus determines which death pathway will be followed. In addition to the release of CXCL8/IL-8, we obtained a massive release of macrophage migration inhibitory factor (MIF) from virus-infected lung cells. However, whereas the CXCL8/IL-8 secretion was accompanied by induced gene activation, the transcription rate of MIF remained unchanged during the infection course and the virus-induced MIF release was predominantly a discharge from intracellular stores, suggesting that MIF is passively released upon cell death. Despite virus induced necrosis, the passively liberated MIF remained bioactive. Considering the well-established immunostimulatory effects of MIF on different leukocyte subsets, is its very likely that enhanced levels of MIF may contribute to the host immune response during the acute phase of influenza A virus infection in humans.