In vivo endotoxin synchronizes and suppresses clock gene expression in human peripheral blood leukocytes.
In vivo endotoxin synchronizes and suppresses clock gene expression in human peripheral blood leukocytes.
复制标题
DOI：
10.1097/ccm.0b013e3181cd131c
复制
发表时间：
2010-03
影响因子：
8.8
通讯作者：
Lowry SF
中科院分区：
文献类型：
--
作者：
Haimovich B;Calvano J;Haimovich AD;Calvano SE;Coyle SM;Lowry SF
The intravenous administration of a bolus dose of endotoxin to healthy human subjects triggers acute systemic inflammatory responses that include cytokine production and dynamic changes in gene expression in peripheral blood leukocytes (PBL). This study sought to determine the state of clock gene expression in human PBL, and leukocytes subpopulations, challenged with in vivo endotoxin at two circadian/diurnal phases of the clock. Clinical and laboratory investigation. University-based research laboratory and clinical research center Human volunteers. Human subjects were administered a standard dose of endotoxin (2ng/kg) or saline at either 09:00 or 21:00 h. Blood samples were collected at selected time points pre- and post-infusion. Clock gene expression was determined in human PBL, neutrophils, and monocytes, by quantitative real-time polymerase chain reaction. The fold change for each gene was determined using the 2(-ΔΔCt) method. We show that endotoxin causes profound suppression of circadian clock gene expression, clearly manifested in human PBL, neutrophils, and monocytes. Clock, Cry1-2, Per3, CSNK1ε, Rora and Rev-erb gene expression were all reduced by 80-90% with the nadir between 3 to 6 hours post-infusion. Per1 and Per2 reached an expression nadir between 13 and 17 hours post-infusion. The levels of plasma interleukin-6 and tumor necrosis factor peaked and then returned to baseline within 6 hours. In contrast, clock gene expression remained suppressed for up to 17 hours, irrespective of the phase of the clock at the time of the endotoxin challenge. Endotoxin did not perturb the melatonin secretory rhythm. Circadian clock gene expression in PBL is dramatically altered, and possibly uncoupled from the activity of the central clock, during periods of acute systemic inflammation. The realignment of the central and peripheral clocks may constitute a previously unappreciated key factor affecting recovery from disease in humans.
