Characterization of the molecular clock in mouse peritoneal macrophages
Characterization of the molecular clock in mouse peritoneal macrophages
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DOI：
10.1248/bpb.30.621
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发表时间：
2007-04-01
影响因子：
2
通讯作者：
Tezuka, Masakatsu
中科院分区：
文献类型：
--
作者：
Hayashi, Mitsuaki;Shimba, Shigeki;Tezuka, Masakatsu
巨噬细胞在先天免疫系统中起着重要作用。在这项研究中，我们表明，巨噬细胞的功能，如吞噬作用和细胞因子/趋化因子的表达显示昼夜节律，是由一个分子钟调节。吞噬作用是巨噬细胞保护其宿主免受外来颗粒侵害的关键早期反应，其表现出昼夜变化，在光照期间达到峰值，在黑暗期间达到底部。这些在巨噬细胞吞噬活性的昼夜变化诱导没有外源性刺激，如细菌感染。包括脑和肌肉Arnt样蛋白-1（BMAL 1）在内的时钟基因的表达在巨噬细胞中表现出强大的昼夜节律。巨噬细胞中时钟基因的表达模式与视交叉上核和其他外周组织中的相似。在所检测的炎症因子中，单核细胞趋化蛋白-1（MCP-1/JE）mRNA的水平表现出最强的昼夜节律振荡。其他细胞因子如IL-1 β、IL-6和TNF α的表达显示出轻微的昼夜变化。BMAL 1表达的下调导致巨噬细胞中MCP-1/JE mRNA水平的降低。BMAL 1显著提高MCP-1/JE启动子活性，但作用较弱。已知MCP-1/JE启动子活性受核因子-κ B（NF-κ B）调节。NF-κ B B活性在BMAL 1敲低的巨噬细胞中低于对照细胞。因此，巨噬细胞中MCP-1/JE的昼夜表达由BMAL 1通过NF-κ B的活化来调节。本研究的结果表明，巨噬细胞参与的先天免疫反应至少部分受自主生物钟机制的调节。
Macrophages play essential roles in the innate immune system. In this study, we show that macrophage functions such as phagocytosis and cytokine/chemokine expressions display a circadian rhythm that is regulated by a molecular clock. Phagocytosis, a crucial early reaction by which macrophages protect their host against foreign particles, exhibited a circadian variation that peaks during the light period and bottoms during the dark period. These diurnal changes of phagocytosis activity in macrophages were induced without exogenous stimulants such as bacterial infection. The expression of the clock genes including brain and muscle Arnt-like protein-1 (BMAL1) exhibited robust circadian rhythms in macrophages. The expression patterns of the clock genes in macrophages were similar to those in the suprachiasmatic nucleus and other peripheral tissues. Among inflammation factors examined, the level of monocyte chemoattractant protein-1 (MCP-1/JE) mRNA exhibited most robust circadian oscillation. Expression of other cytokines such as IL-1 beta, IL-6 and TNF alpha showed mild diurnal changes. Knockdown of the BMAL1 expression resulted in a decrease of the MCP-1/JE mRNA level in macrophages. BMAL1 increased significantly but weakly MCP-1/JE promoter activity. MCP-1/JE promoter activity is known to be regulated by nuclear factor-kappa B (NF-kappa B). NF-kappa B activity in BMAL1 knockdown macrophages was lower than that in control cells. Consequently, the circadian expression of MCP-1/JE in macrophages is regulated by BMAL1 through the activation of NF-kappa B. The results obtained in this study indicate that the innate immunoreactions involving macrophages are at least partly regulated by the autonomous clock machinery.