Endogenous cortisol determines the circadian rhythm of lipopolysaccharide‐ but not lipoteichoic acid‐inducible cytokine release

Abstract

To investigate the circadian rhythm of inducible cytokine release and a potential pacemaker role of endogenous cortisol, cortisol levels as well as cytokine release from ex vivo LPS-stimulated blood were assessed at 4-h intervals over 24 h in 11 volunteers. We found a significant diurnal variation for IFN-c and IL-8, and a tendency for TNF, all inversely correlated to the serum cortisol levels, but no evidence for such a rhythm for IL-1b and IL-6. In vitro IC 50 values for cytokine inhibition by hydrocortisone (HC) corresponded to the observed rank order for circadian rhythmicity. mRNA analyses revealed that this was due to a reduction of gene transcription. These effects of HC were significantly reversed by the glucocorticoid receptor antagonist RU486. Supplementation of HC in vivo to maintain morning cortisol levels throughout the day blunted the circadian rhythm of ex vivo LPS-induced cytokines. Surprisingly, no significant diurnal variation for any investigated cytokine was found in the same volunteer group upon stimulation with lipoteichoic acid (LTA), the gram-positive counterpart to LPS. Furthermore, 10-50-fold higher HC concentrations as compared to LPS were required to block LTA-induced cytokine release. LTA, in contrast to LPS, failed to activate Jun kinase, a reported target for HC action.

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…For IFN-g and IL-2 secretion at baseline, the magnitude of the nocturnal peak is similar when we compare absolute values with values expressed per cell. Although cortisol and its anti-inflammatory properties were proposed to be associated with rhythmic cytokine secretion (cortisol levels are low when cytokine release is high and vice versa) (27,38), studies in rodents (25) and humans (28) indicate a control of the cytokine secretion by the peripheral clocks located in immune cells.…”

“…Among them, the innate and adaptive immune systems were shown to display daily rhythms in rodents and humans (14). This includes rhythms in cell counts in the blood (15)(16)(17)(18) and peripheral lymphoid organs (19), lymphocyte proliferation (20), cytokine levels in the blood (21)(22)(23)(24), and following ex vivo stimulation with various stimuli (16,19,(25)(26)(27)(28).…”

Immune Modulation after Total Hip Surgery

“…This further emphasized the reliability of our study. The stimulation of whole blood with LPS is known to have high diurnal variations [8] . All samples were therefore always taken at 08: 00 h.…”

“…All the samples were taken at 08: 00 h to control for diurnal variation, although there is no significant circadian change in the literature for TNF-␣ or IL-6 [8] . The samples for assessments of ex vivo cytokine responses to endotoxins were immediately placed on ice and anticoagulated in heparin (Leo, 30 IU/ml).…”

Neutrophil homeostasis and its regulation by danger signaling

“…Germ-free mice display excessive marrow basophil granulopoiesis via IL-3 signaling, which in turn depends on MyD88 expression in immunoglobulin E-secreting B cells. 35 Interestingly, response of the innate immune system to microbial compounds is circadian in nature as well: endogenous cortisol levels predetermine cytokine response to LPS in humans, 36 and a MF circadian clockwork controls their inflammatory response. 37 Of note, the circadian-regulated response to PAMPs is not limited to hematopoietic cells but has been characterized in detail in the mutual relationship of intestinal epithelial cells and microbiota.…”