Fas-Mediated Inflammatory Response in Listeria monocytogenes Infection
Fas-Mediated Inflammatory Response in Listeria monocytogenes Infection
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DOI：
10.4049/jimmunol.1203059
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
R. Uchiyama;S. Yonehara;H. Tsutsui
中科院分区：
文献类型：
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作者：
R. Uchiyama;S. Yonehara;H. Tsutsui
人们越来越了解 Fas (CD95/Apo-1) 介导的细胞凋亡的分子机制。然而，Fas 介导的促炎细胞因子（例如 IL-18 和 IL-1β）的产生在细菌感染中的作用尚不清楚。我们证明了 Fas 介导的信号传导在单核细胞增多性李斯特菌感染后产生 IL-18/IL-1β 中的重要性，而无需 caspase-1 炎症小体的参与。 Fas 缺陷小鼠感染单增李斯特菌的腹膜渗出细胞中 IL-18/IL-1β 的产生低于野生型小鼠，表明 Fas 信号传导有助于细胞因子的产生。单增李斯特菌感染诱导 NK 细胞表达 Fas 配体，刺激受感染巨噬细胞表达 Fas，从而产生 IL-18/IL-1β。这独立于 caspase-1、caspase-11 和核苷酸结合域以及富含亮氨酸重复序列的受体 (NLR)，例如 Nlrp3 和 Nlrc4，但依赖于含有 caspase 募集域的凋亡相关斑点样蛋白。野生型细胞表现出 caspase-8 激活，而 Fas 缺陷细胞则没有。单增李斯特菌诱导的 caspase-8 激活被细胞内活性氧抑制剂 N-乙酰基-L-半胱氨酸消除。单增李斯特菌感染的巨噬细胞产生 I 型 IFN，例如 IFN-β1，这是 Il18 基因表达所必需的。因此，Fas 信号传导调节单核细胞增生李斯特菌感染中先天炎症细胞因子的产生。
The molecular mechanisms of Fas (CD95/Apo-1)-mediated apoptosis are increasingly understood. However, the role of Fas-mediated production of proinflammatory cytokines such as IL-18 and IL-1β in bacterial infection is unclear. We demonstrate the importance of Fas-mediated signaling in IL-18/IL-1β production postinfection with Listeria monocytogenes without the contribution of caspase-1 inflammasome. IL-18/IL-1β production in L. monocytogenes–infected peritoneal exudate cells from Fas-deficient mice was lower than those from wild type mice, indicating that Fas signaling contributes to cytokine production. L. monocytogenes infection induced Fas ligand expression on NK cells, which stimulates Fas expressed on the infected macrophages, leading to the production of IL-18/IL-1β. This was independent of caspase-1, caspase-11, and nucleotide-binding domain and leucine-rich repeat–containing receptors (NLRs) such as Nlrp3 and Nlrc4, but dependent on apoptosis-associated speck-like protein containing a caspase recruitment domain. Wild type cells exhibited caspase-8 activation, whereas Fas-deficient cells did not. L. monocytogenes–induced caspase-8 activation was abrogated by inhibitor for intracellular reactive oxygen species, N-acetyl-L-cysteine. L. monocytogenes–infected macrophages produced type-I IFNs such as IFN-β1, which was required for Il18 gene expression. Thus, Fas signaling regulates innate inflammatory cytokine production in L. monocytogenes infection.