Endogenous cortisol determines the circadian rhythm of lipopolysaccharide-- but not lipoteichoic acid--inducible cytokine release.
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-gamma 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-1beta 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.
Hermann
Corinna
C
Biochemical Pharmacology, University of Konstanz, D-78457 Konstanz, Germany. Corinna.hermann@uni-konstanz.de
von Aulock
Sonja
S
Dehus
Oliver
O
Keller
Moritz
M
Okigami
Hiromi
H
Gantner
Florian
F
Wendel
Albrecht
A
Hartung
Thomas
T
D000021:Abortifacient Agents, Steroidal / Q000494:pharmacology; D000328:Adult; D001773:Blood Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D016759:Oncogene Protein p65(gag-jun) / Q000276:immunology / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D000021:Abortifacient Agents, Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D016759:Oncogene Protein p65(gag-jun); D011965:Receptors, Glucocorticoid; D013682:Teichoic Acids; D015735:Mifepristone; C009900:lipoteichoic acid; D006854:Hydrocortisone