瑞典乌普萨拉大学生物医学中心的Julie Gibbs等近日在美国国家科学院院刊（Proceedings of the National Academy of Sciences）发表论文称，发现了连接生物钟与免疫系统的关键基因。改发现或对炎症性疾病的研究有重要意义。
人类和动物均受到生物钟的调节，生物钟基因在日常各种活动的调节过程中具有重要作用。巨噬细胞产生的主要免疫分子每天随生物钟的调节而变化，引起许多炎症性疾病如风湿性关节炎的症状也发生周期性变化。
为阐明生物钟与免疫系统的联系，Julie Gibbs等对联系生物钟与免疫系统的分子机制进行了研究。
研究人员研究了小鼠免疫信号分子即细胞因子在一天中不同时间对细菌毒素的反应，发现一种炎性细胞因子的激活在不同时间内的变异较大。
在破坏小鼠巨噬细胞的一个生物钟关键基因后，该细胞因子和巨噬细胞的这种周期性变化便不再呈现，表明该炎性细胞因子的周期性变化受到巨噬细胞生物钟的调节。
研究者还发现，通过基因方法或药物调节rev-erbα基因的表达可调节炎性细胞因子白细胞介素6（IL-6）的合成和释放，而并不影响巨噬细胞生物钟。因此作者认为，rev-erbα基因在连接生物钟和免疫功能中起关键作用。（生物谷bioon.com）
doi:10.1073/pnas.1106750109
PMC:
PMID:
The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines
Julie E. Gibbsa,1, John Blaikleya,1, Stephen Beesleya, Laura Matthewsa, Karen D. Simpsonb, Susan H. Boyceb, Stuart N. Farrowb, Kathryn J. Elsea, Dave Singhc, David W. Raya,2, and Andrew S. I. Loudona,2
Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erbα expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERBα activity. Circadian gating of endotoxin response was lost in rev-erbα−/− mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erbα expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease.
