Williams Julie A, Sathyanarayanan Sriram, Hendricks Joan C, Sehgal Amita
Center for Advanced Biotechnology and Medicine and Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Piscataway 08854-5603, USA.
Sleep. 2007 Apr;30(4):389-400. doi: 10.1093/sleep/30.4.389.
The regulation of sleep is poorly understood. While some molecules, including those involved in inflammatory/immune responses, have been implicated in the control of sleep, their role in this process remains unclear. The Drosophila model for sleep provides a powerful system to identify and test the role of sleep-relevant molecules.
We conducted an unbiased screen for molecular candidates involved in sleep regulation by analyzing genome-wide changes in gene expression associated with sleep deprivation in Drosophila. To further examine a role of immune-related genes identified in the screen, we performed molecular assays, analysis of sleep behavior in relevant mutant and transgenic flies, and quantitative analysis of the immune response following sleep deprivation.
A major class of genes that increased expression with sleep deprivation was that involved in the immune response. We found that immune genes were also upregulated during baseline conditions in the cyc01 sleep mutant. Since the expression of an NFkappaB, Relish, a central player in the inflammatory response, was increased with all manipulations that reduced sleep, we focused on this gene. Flies deficient in, but not lacking, Relish expression exhibited reduced levels of nighttime sleep, supporting a role for Relish in the control of sleep. This mutant phenotype was rescued by expression of a Relish transgene in fat bodies, which are the major site of inflammatory responses in Drosophila. Finally, sleep deprivation also affected the immune response, such that flies deprived of sleep for several hours were more resistant to bacterial infection than those flies not deprived of sleep.
These results demonstrate a conserved interaction between sleep and the immune system. Genetic manipulation of an immune component alters sleep, and likewise, acute sleep deprivation alters the immune response.
睡眠调节机制仍未被充分理解。虽然一些分子，包括那些参与炎症/免疫反应的分子，已被认为与睡眠控制有关，但其在这一过程中的作用仍不清楚。果蝇睡眠模型为识别和测试与睡眠相关分子的作用提供了一个强大的系统。
我们通过分析果蝇睡眠剥夺相关的全基因组基因表达变化，对参与睡眠调节的分子候选物进行了无偏筛选。为了进一步研究筛选中鉴定出的免疫相关基因的作用，我们进行了分子检测、相关突变体和转基因果蝇的睡眠行为分析，以及睡眠剥夺后免疫反应的定量分析。
一类随着睡眠剥夺而表达增加的主要基因是参与免疫反应的基因。我们发现，在cyc01睡眠突变体的基线条件下，免疫基因也会上调。由于炎症反应的核心参与者NFκB（Relish）的表达随着所有减少睡眠的操作而增加，我们将重点放在了这个基因上。缺乏（但并非完全没有）Relish表达的果蝇夜间睡眠水平降低，这支持了Relish在睡眠控制中的作用。在脂肪体（果蝇炎症反应的主要部位）中表达Relish转基因可挽救该突变体表型。最后，睡眠剥夺也影响免疫反应，使得被剥夺睡眠数小时的果蝇比未被剥夺睡眠的果蝇对细菌感染更具抵抗力。
这些结果表明睡眠与免疫系统之间存在保守的相互作用。对免疫成分的基因操作会改变睡眠，同样，急性睡眠剥夺也会改变免疫反应。
