OBJECTIVES: 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. This study sought to determine the state of clock gene expression in human peripheral blood leukocytes, and leukocyte subpopulations, challenged with in vivo endotoxin at two circadian/diurnal phases of the clock. DESIGN: Clinical and laboratory investigation. SETTING: University-based research laboratory and clinical research center. SUBJECTS: Human volunteers. INTERVENTIONS: Human subjects were administered a standard dose of endotoxin (2 ng/kg) or saline at either 0900 or 2100 hrs. Blood samples were collected at selected time points pre- and postinfusion. MEASUREMENTS AND MAIN RESULTS: Clock gene expression was determined in human peripheral blood leukocytes, neutrophils, and monocytes by quantitative real-time polymerase chain reaction. The fold change for each gene was determined by use of the 2 method. We show that endotoxin causes profound suppression of circadian clock gene expression, clearly manifested in human peripheral blood leukocytes, neutrophils, and monocytes. Clock, Cry1-2, Per3, CSNK1epsilon, Rora, and Rev-erb gene expression were all reduced by 80% to 90% with the nadir between 3 and 6 hrs postinfusion. Per1 and Per2 reached an expression nadir between 13 and 17 hrs postinfusion. The levels of plasma interleukin-6 and tumor necrosis factor peaked and then returned to baseline within 6 hrs. In contrast, clock gene expression remained suppressed for up to 17 hrs irrespective of the phase of the clock at the time of the endotoxin challenge. Endotoxin did not perturb the melatonin secretory rhythm. CONCLUSIONS: Circadian clock gene expression in peripheral blood leukocytes 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.
OBJECTIVES: 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. This study sought to determine the state of clock gene expression in human peripheral blood leukocytes, and leukocyte subpopulations, challenged with in vivo endotoxin at two circadian/diurnal phases of the clock. DESIGN: Clinical and laboratory investigation. SETTING: University-based research laboratory and clinical research center. SUBJECTS:Human volunteers. INTERVENTIONS:Human subjects were administered a standard dose of endotoxin (2 ng/kg) or saline at either 0900 or 2100 hrs. Blood samples were collected at selected time points pre- and postinfusion. MEASUREMENTS AND MAIN RESULTS:Clock gene expression was determined in human peripheral blood leukocytes, neutrophils, and monocytes by quantitative real-time polymerase chain reaction. The fold change for each gene was determined by use of the 2 method. We show that endotoxin causes profound suppression of circadian clock gene expression, clearly manifested in human peripheral blood leukocytes, neutrophils, and monocytes. Clock, Cry1-2, Per3, CSNK1epsilon, Rora, and Rev-erb gene expression were all reduced by 80% to 90% with the nadir between 3 and 6 hrs postinfusion. Per1 and Per2 reached an expression nadir between 13 and 17 hrs postinfusion. The levels of plasma interleukin-6 and tumor necrosis factor peaked and then returned to baseline within 6 hrs. In contrast, clock gene expression remained suppressed for up to 17 hrs irrespective of the phase of the clock at the time of the endotoxin challenge. Endotoxin did not perturb the melatonin secretory rhythm. CONCLUSIONS: Circadian clock gene expression in peripheral blood leukocytes 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.
Authors: Ruth A Akhtar; Akhilesh B Reddy; Elizabeth S Maywood; Jonathan D Clayton; Verdun M King; Andrew G Smith; Timothy W Gant; Michael H Hastings; Charalambos P Kyriacou Journal: Curr Biol Date: 2002-04-02 Impact factor: 10.834
Authors: Panteleimon D Mavroudis; Jeremy D Scheff; Steve E Calvano; Stephen F Lowry; Ioannis P Androulakis Journal: Physiol Genomics Date: 2012-04-17 Impact factor: 3.107
Authors: Avelino C Verceles; Leann Silhan; Michael Terrin; Giora Netzer; Carl Shanholtz; Steven M Scharf Journal: Intensive Care Med Date: 2012-05 Impact factor: 17.440
Authors: Jeremy D Scheff; Panteleimon D Mavroudis; Steven E Calvano; Stephen F Lowry; Ioannis P Androulakis Journal: Physiol Genomics Date: 2011-06-14 Impact factor: 3.107
Authors: Sarah Kirsch; Stephan Thijssen; Susana Alarcon Salvador; Gunnar H Heine; Kai van Bentum; Danilo Fliser; Martina Sester; Urban Sester Journal: J Clin Immunol Date: 2012-07-15 Impact factor: 8.317
Authors: Martin Lopez; Daniel Meier; Andreas Müller; Paul Franken; Jun Fujita; Adriano Fontana Journal: J Biol Chem Date: 2013-12-11 Impact factor: 5.157
Authors: Kord M Kober; Laura Dunn; Judy Mastick; Bruce Cooper; Dale Langford; Michelle Melisko; Alan Venook; Lee-May Chen; Fay Wright; Marilyn Hammer; Brian L Schmidt; Jon Levine; Christine Miaskowski; Bradley E Aouizerat Journal: Biol Res Nurs Date: 2016-03-08 Impact factor: 2.522
Authors: Jeremy D Scheff; Panteleimon D Mavroudis; Steve E Calvano; Ioannis P Androulakis Journal: J Clin Monit Comput Date: 2012-12-01 Impact factor: 2.502