Hayashi Mitsuaki, Shimba Shigeki, Tezuka Masakatsu
Department of Health Science, College of Pharmacy, Nihon University, Japan.
Biol Pharm Bull. 2007 Apr;30(4):621-6. doi: 10.1248/bpb.30.621.
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-1beta, IL-6 and TNFalpha 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-kappaB). NF-kappaB 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-kappaB. The results obtained in this study indicate that the innate immunoreactions involving macrophages are at least partly regulated by the autonomous clock machinery.
巨噬细胞在固有免疫系统中发挥着重要作用。在本研究中，我们发现巨噬细胞的吞噬作用以及细胞因子/趋化因子表达等功能呈现出昼夜节律，且该节律受分子钟调控。吞噬作用是巨噬细胞保护宿主抵御外来颗粒的关键早期反应，呈现出昼夜变化，在光照期达到峰值，在黑暗期降至谷底。巨噬细胞吞噬活性的这些昼夜变化是在没有诸如细菌感染等外源性刺激的情况下诱导产生的。包括脑和肌肉芳香烃受体核转运蛋白样蛋白1（BMAL1）在内的生物钟基因在巨噬细胞中呈现出强烈的昼夜节律。巨噬细胞中生物钟基因的表达模式与视交叉上核及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水平呈现出最强烈的昼夜振荡。其他细胞因子如白细胞介素-1β、白细胞介素-6和肿瘤坏死因子α的表达则呈现出轻微的昼夜变化。敲低BMAL1的表达导致巨噬细胞中MCP-1/JE mRNA水平降低。BMAL1可显著但微弱地增加MCP-1/JE启动子活性。已知MCP-1/JE启动子活性受核因子κB（NF-κB）调控。BMAL1敲低的巨噬细胞中NF-κB活性低于对照细胞。因此，巨噬细胞中MCP-1/JE的昼夜表达是由BMAL1通过激活NF-κB来调控的。本研究所得结果表明，涉及巨噬细胞的固有免疫反应至少部分受自主生物钟机制调控。
