Rabies virus stimulates nitric oxide production and CXC chemokine ligand 10 expression in macrophages through activation of extracellular signal-regulated kinases 1 and 2
Rabies virus stimulates nitric oxide production and CXC chemokine ligand 10 expression in macrophages through activation of extracellular signal-regulated kinases 1 and 2
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DOI：
10.1128/jvi.78.17.9376-9388.2004
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发表时间：
2004-09-01
影响因子：
5.4
通讯作者：
Kurane, I
中科院分区：
文献类型：
--
作者：
Nakamichi, K;Inoue, S;Kurane, I
巨噬细胞是天然免疫的重要组成部分，病毒感染巨噬细胞可导致多种促炎介质的释放，如一氧化氮(NO)、细胞因子和趋化因子等。本研究旨在探讨狂犬病病毒(RV)感染后巨噬细胞活化的分子机制。在RAW264小鼠巨噬细胞中，RV的复制受到严格限制，而RV接种后细胞的增殖显著增强。对诱导型一氧化氮合酶(INOS)、细胞因子和趋化因子表达的转录分析表明，RV病毒粒子增强了iNOS和CXC趋化因子配体10(CXCL10)的基因表达，而RV刺激对促炎细胞因子和其他类型趋化因子的表达几乎没有影响。在紫外线灭活的轮状病毒粒子和感染性病毒刺激的巨噬细胞中，细胞外信号调节蛋白激酶(ERK)1和2的磷酸化被显著诱导，ERK是丝裂原激活的蛋白激酶家族的成员。MAPK/ERK激酶的特异性抑制剂可减少RV诱导的NO和CXCL10的产生。此外，内吞作用是ERK1/2信号通路激活的关键步骤，内吞作用是ERK1/2信号通路激活的关键步骤。综上所述，这些结果表明ERK1/2介导的信号通路在RV病毒粒子选择性激活巨噬细胞，从而调节病毒感染过程中的细胞功能方面起着重要作用。
Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.