Agorastos Agorastos1, Richard L Hauger2, Donald A Barkauskas3, Tobias Moeller-Bertram2, Paul L Clopton4, Uzair Haji4, James B Lohr2, Thomas D Geracioti5, Piyush M Patel6, George P Chrousos7, Dewleen G Baker8. 1. 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. 2. 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. 3. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 4. VA San Diego Healthcare System, San Diego, CA, USA. 5. Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA. 6. VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA. 7. First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Athens, Greece. 8. 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.
Abstract
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. Published by Elsevier Ltd.
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. Published by Elsevier Ltd.
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