瑞典烏普薩拉大學(xué)生物醫(yī)學(xué)中心的Julie Gibbs等近日在美國國家科學(xué)院院刊（Proceedings of the National Academy of Sciences）發(fā)表論文稱,，發(fā)現(xiàn)了連接生物鐘與免疫系統(tǒng)的關(guān)鍵基因。改發(fā)現(xiàn)或?qū)ρ装Y性疾病的研究有重要意義,。
人類和動物均受到生物鐘的調(diào)節(jié),，生物鐘基因在日常各種活動的調(diào)節(jié)過程中具有重要作用。巨噬細(xì)胞產(chǎn)生的主要免疫分子每天隨生物鐘的調(diào)節(jié)而變化,，引起許多炎癥性疾病如風(fēng)濕性關(guān)節(jié)炎的癥狀也發(fā)生周期性變化,。
為闡明生物鐘與免疫系統(tǒng)的聯(lián)系，Julie Gibbs等對聯(lián)系生物鐘與免疫系統(tǒng)的分子機(jī)制進(jìn)行了研究,。
研究人員研究了小鼠免疫信號分子即細(xì)胞因子在一天中不同時間對細(xì)菌毒素的反應(yīng),，發(fā)現(xiàn)一種炎性細(xì)胞因子的激活在不同時間內(nèi)的變異較大。
在破壞小鼠巨噬細(xì)胞的一個生物鐘關(guān)鍵基因后,，該細(xì)胞因子和巨噬細(xì)胞的這種周期性變化便不再呈現(xiàn),，表明該炎性細(xì)胞因子的周期性變化受到巨噬細(xì)胞生物鐘的調(diào)節(jié)。
研究者還發(fā)現(xiàn),，通過基因方法或藥物調(diào)節(jié)rev-erbα基因的表達(dá)可調(diào)節(jié)炎性細(xì)胞因子白細(xì)胞介素6（IL-6）的合成和釋放,，而并不影響巨噬細(xì)胞生物鐘。因此作者認(rèn)為,，rev-erbα基因在連接生物鐘和免疫功能中起關(guān)鍵作用,。（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.
