Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome

Psychoneuroendocrinology. 2005 Feb;30(2):188-98. doi: 10.1016/j.psyneuen.2004.06.008.


Objective: It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls.

Method: Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test.

Results: CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels.

Conclusion: CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial

MeSH terms

  • Adrenocorticotropic Hormone / analysis
  • Adrenocorticotropic Hormone / blood
  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Chi-Square Distribution
  • Cytokines / blood*
  • Fatigue Syndrome, Chronic / blood
  • Fatigue Syndrome, Chronic / immunology*
  • Fatigue Syndrome, Chronic / psychology
  • Female
  • Humans
  • Hydrocortisone / analysis
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / immunology
  • Hypothalamo-Hypophyseal System / physiopathology
  • Interleukin-6 / blood
  • Lipopolysaccharides / immunology
  • Male
  • Matched-Pair Analysis
  • Middle Aged
  • Neuroimmunomodulation / physiology*
  • Pituitary-Adrenal System / immunology
  • Pituitary-Adrenal System / physiopathology
  • Psychometrics
  • Saliva / chemistry
  • Stress, Psychological / blood
  • Stress, Psychological / immunology*
  • Tumor Necrosis Factor-alpha / analysis


  • Cytokines
  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Adrenocorticotropic Hormone
  • Hydrocortisone