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Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans.

ABSTRACT: To define gene expression profiles that occur during the initial activation of human innate immunity, we administered intravenous endotoxin (n = 8) or saline (n = 4) to healthy subjects and hybridized RNA from blood mononuclear cells (0, 0.5, 6, 24, 168 h) or whole blood (0, 3, 6, 24, 168 h) to oligonucleotide probe arrays. The greatest change in mononuclear cell gene expression occurred at 6 h (439 induced and 428 repressed genes, 1% false discovery rate, and 50% fold change) including increased expression of genes associated with pathogen recognition molecules and signaling cascades linked to receptors associated with cell mobility and activation. Induced defense response genes included cytokines, chemokines, and their respective receptors, acute-phase transcription factors, proteases, arachidonate metabolites, and oxidases. Repressed defense response genes included those associated with co-stimulatory molecules, T and cytotoxic lymphocytes, natural killer (NK) cells, and protein synthesis. Gene expression profiles of whole blood had similar biological themes. Over 100 genes not typically associated with acute inflammation were differentially regulated after endotoxin. By 24 h, gene expression had returned to baseline values. Thus the inflammatory response of circulating leukocytes to endotoxin in humans is characterized by a rapid amplification and subsidence of gene expression. These results indicate that a single intravascular exposure to endotoxin produces a large but temporally short perturbation of the blood transcriptome.

SUBMITTER: Talwar S

PROVIDER: S-EPMC5560445 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans.

Talwar Shefali S Munson Peter J PJ Barb Jennifer J Fiuza Carmen C Cintron Anadel Pilar AP Logun Carolea C Tropea Margaret M Khan Sameena S Reda Debra D Shelhamer James H JH Danner Robert L RL Suffredini Anthony F AF

Physiological genomics 20060110 2

To define gene expression profiles that occur during the initial activation of human innate immunity, we administered intravenous endotoxin (n = 8) or saline (n = 4) to healthy subjects and hybridized RNA from blood mononuclear cells (0, 0.5, 6, 24, 168 h) or whole blood (0, 3, 6, 24, 168 h) to oligonucleotide probe arrays. The greatest change in mononuclear cell gene expression occurred at 6 h (439 induced and 428 repressed genes, 1% false discovery rate, and 50% fold change) including increase ...[more]

PMID: 16403844

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Project description:ObjectivesThe 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.DesignClinical and laboratory investigation.SettingUniversity-based research laboratory and clinical research center.SubjectsHuman volunteers.InterventionsHuman 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 resultsClock 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.ConclusionsCircadian 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.

Project description:Background:The aim of the present study was to evaluate CCL8 and CXCL10 expression and its regulatory mechanism in peripheral blood leukocytes (PBLs) at the time of maternal recognition in cows. Blood samples were collected on 14, 15, 16, 17 and 18 d after artificial insemination (AI). Based on the day of return of estrus, cows were divided into three groups, pregnant (n =?5), early embryonic mortality (EEM; n =?5) and late embryonic mortality (LEM; n =?5). The gene expression levels in PBLs were assessed with quantitative real-time reverse transcription PCR. Results:The expression of CCL8 and CXCL10 mRNA in PBLs gradually increased from 14 to 18 d of pregnant cows and significant differences were observed on 18 d (P <?0.05), whereas no significant changes were observed both in EEM and LEM cows. Interferon-stimulated protein 15 kDa (ISG15), myxovirus-resistance gene (MX) 1 and MX2 mRNA expression in PBLs increased from 14 to 18 d which was significant on 18 d of pregnant cows as well as in LEM cows (P <?0.05), but no changes were observed in EEM cows. To determine whether the expression of CCL8 and CXCL10 in PBLs was regulated by pregnancy-related substances or not, expression level was assessed after exposure to interferon-? (IFNT) and CCL16. Monocytes, granulocytes and lymphocytes were obtained using density-gradient centrifugation and flow cytometry. The addition of IFNT (100 ng/mL) and CCL16 (100 ng/mL) to cultured PBLs increased the expression of CCL8 and CXCL10 mRNA (P <?0.05). The expression of ISG15, MX1 and MX2 mRNA in PBLs was also stimulated by IFNT and CCL16 (P <?0.05). Conclusions:The expression of CCL8 and CXCL10 genes increased in PBLs during early pregnancy. Since IFNT stimulated CCL8 and CXCL10 expression in cultured PBLs, the increase of CCL8 and CXCL10 might be pregnancy-dependent events. The expression of both CCL8 and CXCL10 in PBLs was stimulated by CCL16 as well as IFNT, suggesting a chemokine interaction that at least includes CCL8, CXCL10 and CCL16, and may play a role in regulating maternal recognition in cows.

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Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans.

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Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans.

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