Circadian rhythmicity, variability and correlation of interleukin-6 levels in plasma and cerebrospinal fluid of healthy men.
BACKGROUND
Interleukin-6 (IL-6) is a cytokine with pleiotropic actions in both the periphery of the body and the central nervous system (CNS). Altered IL-6 secretion has been associated with inflammatory dysregulation and several adverse health consequences. However, little is known about the physiological circadian characteristics and dynamic inter-correlation between circulating and CNS IL-6 levels in humans, or their significance.


METHODS
Simultaneous assessment of plasma and cerebrospinal fluid (CSF) IL-6 levels was performed hourly in 11 healthy male volunteers over 24h, to characterize physiological IL-6 secretion levels in both compartments.


RESULTS
IL-6 levels showed considerable within- and between-subject variability in both plasma and CSF, with plasma/CSF ratios revealing consistently higher levels in the CSF. Both CSF and plasma IL-6 levels showed a distinctive circadian variation, with CSF IL-6 levels exhibiting a main 24h, and plasma a biphasic 12h, circadian component. Plasma peaks were roughly at 4 p.m. and 4 a.m., while the CSF peak was at around 7 p.m. There was no correlation between coincident CSF and plasma IL-6 values, but evidence for significant correlations at a negative 7-8h time lag.


CONCLUSIONS
This study provides evidence in humans for a circadian IL-6 rhythm in CSF and confirms prior observations reporting a plasma biphasic circadian pattern. Our results indicate differential IL-6 regulation across the two compartments and are consistent with local production of IL-6 in the CNS. Possible physiological significance is discussed and implications for further research are highlighted.
VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA; Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Agorastos
A
Agorastos
VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA.
Richard L
RL
Hauger
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Donald A
DA
Barkauskas
VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA.
Tobias
T
Moeller-Bertram
VA San Diego Healthcare System, San Diego, CA, USA.
Paul L
PL
Clopton
VA San Diego Healthcare System, San Diego, CA, USA.
Uzair
U
Haji
VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA.
James B
JB
Lohr
Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA.
Thomas D
TD
Geracioti
VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA.
Piyush M
PM
Patel
First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Athens, Greece.
George P
GP
Chrousos
VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA. Electronic address: dgbaker@ucsd.edu.
Dewleen G
DG
Baker
D000328:Adult; D002940:Circadian Rhythm / Q000502:physiology*; D064368:Healthy Volunteers; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D055815:Young Adult
D015850:Interleukin-6
Blood–brain-barrier (BBB); Cerebrospinal fluid (CSF); Circadian; Cytokines; Immune; Inflammation; Interleukin-6 (IL-6); Neuroimmunology; Sleep; Stress