Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin O, after evasion from phagosome into the cytoplasm
Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin O, after evasion from phagosome into the cytoplasm
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DOI：
10.4049/jimmunol.180.12.7859
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发表时间：
2008-06-15
影响因子：
4.4
通讯作者：
Mitsuyama, Masao
中科院分区：
文献类型：
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作者：
Hara, Hideki;Tsuchiya, Kohsuke;Mitsuyama, Masao
李斯特菌溶血素O（LLO）是单核细胞增生李斯特菌（Listeria monocytogenes）的一种溶血素，在李斯特菌进入巨噬细胞胞质过程中起重要作用，也是在感染的先天免疫阶段诱导IFN-γ产生的关键因子。在这项研究中，我们研究了LLO参与巨噬细胞产生IFN-γ诱导的细胞因子IL-12和IL-18。巨噬细胞在感染野生型单核细胞增多性李斯特菌后产生显著水平的IL-12和IL-18，而LLO缺陷型突变体（LLO突变体）在感染LLO后产生显著水平的IL-12和IL-18。单核细胞增多症Δ hly）缺乏诱导IL-18产生的能力。Δ hly与hly互补完全恢复了这种能力。然而，当Δ hly与编码ivanolysin O（ILO）的ILO（一种与LLO高度同源的溶细胞素）互补时，没有观察到这种恢复，尽管表达Δ hly的L.单核细胞增多症在巨噬细胞胞质中的侵入和增殖与表达LLO的L.单核细胞增多症当用半胱天冬酶-1抑制剂预处理或在半胱天冬酶-1缺陷小鼠的巨噬细胞中时，IL-18的诱导减少，表明半胱天冬酶-1的活化是导致IL-18产生的关键事件。caspase-1的激活诱导的巨噬细胞感染的LLO表达单核细胞增生李斯特菌，但不是在那些与δ hly。即使在与ILO基因互补后也不能观察到这种活性的完全恢复。这些结果表明，LLO分子参与caspase-1的活化，这是必不可少的IL-18的生产在感染的巨噬细胞，并表明，一些序列独特的LLO是必不可少的一些信号事件，导致caspase-1激活单核细胞增生李斯特菌诱导。
Listeriolysin O (LLO), an hly-encoded cytolysin from Listeria monocytogenes, plays an essential role in the entry of this pathogen into the macrophage cytoplasm and is also a key factor in inducing the production of IFN-gamma during the innate immune stage of infection. In this study, we examined the involvement of LLO in macrophage production of the IFN-gamma-inducing cytokines IL-12 and IL-18. Significant levels of IL-12 and IL-18 were produced by macrophages upon infection with wild-type L monocytogenes, whereas an LLO-deficient mutant (the L. monocytogenes Delta hly) lacked the ability to induce IL-18 production. Complementation of Delta hly with hly completely restored the ability. However, when Delta hly was complemented with ilo encoding ivanolysin O (ILO), a cytolysin highly homologous with LLO, such a restoration was not observed, although ILO-expressing L. monocytogenes invaded and multiplied in the macrophage cytoplasm similarly as LLO-expressing L. monocytogenes. Induction of IL-18 was diminished when pretreated with a caspase-1 inhibitor or in macrophages from caspase-1-deficient mice, suggesting the activation of caspase-1 as a key event resulting in IL-18 production. Activation of caspase-1 was induced in macrophages infected with LLO-expressing L monocytogenes but not in those with Delta hly. A complete restoration of such an activity could not be observed even after complementation with the ILO gene. These results show that the LLO molecule is involved in the activation of caspase-1, which is essential for IL-18 production in infected macrophages, and suggest that some sequence unique to LLO is indispensable for some signaling event resulting in the caspase-1 activation induced by L monocytogenes.