Relations of combat stress and posttraumatic stress disorder to 24-h plasma and cerebrospinal fluid interleukin-6 levels and circadian rhythmicity

Psychoneuroendocrinology. 2019 Feb;100:237-245. doi: 10.1016/j.psyneuen.2018.09.009. Epub 2018 Sep 10.


Background: Acute and chronic stress can lead to a dysregulation of the immune response. Growing evidence suggests peripheral immune dysregulation and low-grade systemic inflammation in posttraumatic stress disorder (PTSD), with numerous reports of elevated plasma interleukin-6 (IL-6) levels. However, only a few studies have assessed IL-6 levels in the cerebrospinal fluid (CSF). Most of those have used single time-point measurements, and thus cannot take circadian level variability and CSF-plasma IL-6 correlations into account.

Methods: This study used time-matched, sequential 24-h plasma and CSF measurements to investigate the effects of combat stress and PTSD on physiologic levels and biorhythmicity of IL-6 in 35 male study volunteers, divided in 3 groups: (PTSD = 12, combat controls, CC = 12, and non-deployed healthy controls, HC = 11).

Results: Our findings show no differences in diurnal mean concentrations of plasma and CSF IL-6 across the three comparison groups. However, a significantly blunted circadian rhythm of plasma IL-6 across 24 h was observed in all combat-zone deployed participants, with or without PTSD, in comparison to HC. CSF IL-6 rhythmicity was unaffected by combat deployment or PTSD.

Conclusions: Although no significant group differences in mean IL-6 concentration in either CSF or plasma over a 24-h timeframe was observed, we provide first evidence for a disrupted peripheral IL-6 circadian rhythm as a sequel of combat deployment, with this disruption occurring in both PTSD and CC groups. The plasma IL-6 circadian blunting remains to be replicated and its cause elucidated in future research.

Keywords: Blood-brain-barrier; Cerebrospinal fluid (CSF); Circadian system; Cytokines; Immune system; Interleukin-6 (IL-6); Neuroimmunomodulation; Plasma; Posttraumatic stress disorder (PTSD); Serial sampling; Stress; Trauma.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Case-Control Studies
  • Circadian Rhythm / physiology*
  • Combat Disorders / blood*
  • Combat Disorders / cerebrospinal fluid*
  • Combat Disorders / psychology
  • Humans
  • Interleukin-6* / analysis
  • Interleukin-6* / blood
  • Interleukin-6* / cerebrospinal fluid
  • Male
  • Military Personnel / psychology
  • Stress Disorders, Post-Traumatic / blood*
  • Stress Disorders, Post-Traumatic / cerebrospinal fluid*
  • Veterans / psychology
  • Young Adult


  • Interleukin-6