Liu Jianguo, Malkani Gautam, Shi Xiaoyan, Meyer Mark, Cunningham-Runddles Susana, Ma Xiaojing, Sun Zhong Sheng
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
Infect Immun. 2006 Aug;74(8):4750-6. doi: 10.1128/IAI.00287-06.
The Period 2 (Per2) gene is a key molecular component in controlling mammalian circadian rhythms at the levels of gene expression, physiology, and pathogenesis. Although many immune parameters, such as the number of different subtypes of circulating immune cells and the level of cytokine production in response to infection with bacteria and viruses, have been well documented to display a circadian pattern in mammals, the basic features of molecular clock components in the immune system and the role of clock genes in regulating host immune defenses remain uncharacterized. Previously, we have reported that circadian clock genes oscillate in human mononuclear cells. Here we report that Per2-deficient mice were more resistant to lipopolysaccharide (LPS)-induced endotoxic shock than control wild-type mice. We further demonstrate that the levels of the proinflammatory cytokines gamma interferon (IFN-gamma) and interleukin-1beta (IL-1beta) in the serum were dramatically decreased in Per2-/- mice following LPS challenge, while production of tumor necrosis factor alpha, IL-6, and IL-10 was approximately normal, compared to that in control wild-type mice. Flow cytometric analyses confirmed that the cellularity of most of the immune cell subsets in the spleens of LPS-challenged mice was normal and that the impaired IFN-gamma production in Per2-/- mice was attributable to defective NK and NKT cell function. Our data suggest that Per2 is an important regulator of NK cell function, therefore providing the first direct link between the circadian clock system and innate immune responses.
周期蛋白2（Per2）基因是在基因表达、生理和发病机制水平上控制哺乳动物昼夜节律的关键分子成分。尽管许多免疫参数，如循环免疫细胞不同亚型的数量以及对细菌和病毒感染产生的细胞因子水平，在哺乳动物中已被充分证明呈现昼夜节律模式，但免疫系统中分子时钟成分的基本特征以及时钟基因在调节宿主免疫防御中的作用仍未明确。此前，我们报道过昼夜节律时钟基因在人单核细胞中振荡。在此我们报告，与对照野生型小鼠相比，Per2基因缺陷型小鼠对脂多糖（LPS）诱导的内毒素休克更具抵抗力。我们进一步证明，LPS攻击后，Per2基因敲除小鼠血清中促炎细胞因子γ干扰素（IFN-γ）和白细胞介素-1β（IL-1β）的水平显著降低，而与对照野生型小鼠相比，肿瘤坏死因子α、IL-6和IL-10的产生大致正常。流式细胞术分析证实，LPS攻击小鼠脾脏中大多数免疫细胞亚群的细胞数量正常，且Per2基因敲除小鼠中IFN-γ产生受损归因于NK细胞和NKT细胞功能缺陷。我们的数据表明，Per2是NK细胞功能的重要调节因子，因此首次在昼夜节律时钟系统与固有免疫反应之间建立了直接联系。
