Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-α induction pathway
Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-α induction pathway
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DOI：
10.1073/pnas.0308368101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Falck-Pedersen, E
中科院分区：
文献类型：
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作者：
Philpott, NJ;Nociari, M;Falck-Pedersen, E
在多种动物模型中，系统给药腺病毒和腺病毒载体诱导了强大的先天和适应性免疫反应。在肿瘤坏死因子（TNF）（-/-）小鼠中，对腺病毒（Ad）感染的免疫反应减弱归因于树突状细胞（DC）成熟受损。在本报告中，我们研究了ad介导的DC激活和成熟的机制。Ad感染通过小鼠骨髓源性DC诱导高水平的tnf - α表达，与脂多糖暴露观察到的水平相当。ad诱导的tnf - α的产生是DC成熟所必需的，并且以自分泌的方式起作用。与暴露于脂多糖相关的tnf - α产生不同，Ad诱导tnf - α不依赖于MyD88信号通路。相比之下，通过wortmannin和LY294002阻断实验确定，ad诱导的tnf - α产生和DC成熟依赖于磷酸肌醇-3- oh激酶（PI3K）的信号传导。腺病毒衣壳蛋白penton含有一个特性良好的精氨酸-甘氨酸-天冬氨酸整合素结合域，可刺激成纤维细胞系的PI3K。当该区域突变时，tnf - α表达和骨髓源性DC成熟减弱。我们认为整合素介导的PI3K诱导NF-kappaB激活了DC成熟响应Ad所需的自分泌TNF-a途径。
Systemic administration of adenovirus and adenovirus vectors induces a robust innate and adaptive immune response in a variety of animal models. In tumor necrosis factor (TNF)(-/-) mice, a diminished immune response to adenovirus (Ad) infection has been attributed to compromised dendritic cell (DC) maturation. In this report, we investigated the mechanisms responsible for Ad-mediated activation and maturation of DC. Ad infection induced high levels of TNF-alpha expression by murine bone marrow-derived DC, comparable to levels observed with lipopolysaccharide exposure. Ad-induced TNF-alpha production was necessary for DC maturation and acts in an autocrine manner. Unlike TNF-alpha production associated with exposure to lipopolysaccharide, Ad induction of TNF-alpha was not dependent on the MyD88 signaling pathway. In contrast, Ad-induced TNF-alpha production and DC maturation were dependent on signaling by phosphoinositide-3-OH kinase (PI3K), as determined by wortmannin and LY294002 blocking experiments. The adenovirus capsid protein penton contains a well characterized arginine-glycine-aspartic acid integrin-binding domain that stimulates PI3K in fibroblast cell lines. When this region of the penton was mutated, TNF-alpha expression and bone marrow-derived DC maturation were attenuated. We propose that integrin-mediated PI3K induction of NF-kappaB activates an autocrine TNF-a pathway required for DC maturation in response to Ad.