Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue

Brain Behav Immun. 2008 Jan;22(1):24-32. doi: 10.1016/j.bbi.2007.06.013. Epub 2007 Aug 15.


Objectives: This study examined whether chronic interpersonal stress is associated with cellular markers of inflammation and regulation of these responses by in vitro doses of glucocorticoids in rheumatoid arthritis (RA) patients. The association between these markers of inflammation and fatigue was also tested.

Methods: Fifty-eight RA patients completed up to 30 daily ratings of the stressfulness of their interpersonal relations. Interleukin-6 (IL-6) production was analyzed in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cell cultures with and without varying concentrations of the glucocorticoid hydrocortisone. In addition, plasma levels of IL-6 and C-reactive protein (CRP) were analyzed, and subjective ratings of fatigue and pain were obtained on the day of blood sampling.

Results: Multilevel modeling showed that higher chronic interpersonal stress was associated with greater stimulated IL-6 production (p<0.05) as well as greater resistance to hydrocortisone inhibition of IL-6 production (p<0.05). These relations were not accounted for by demographic factors, body mass index, or steroid medication use. Stimulated production of IL-6, in turn, was associated with greater levels of self-reported fatigue, controlling for pain (p<0.05). Neither chronic stress ratings nor fatigue symptoms were related to plasma levels of IL-6 or CRP (ps>.05).

Conclusions: Among RA patients, chronic interpersonal stress is associated with greater stimulated cellular production of IL-6 along with impairments in the capacity of glucocorticoids to inhibit this cellular inflammatory response. Moreover, these findings add to a growing body of data that implicate heightened proinflammatory cytokine activity in those at risk for fatigue symptoms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents / pharmacology
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / complications*
  • Biomarkers / blood*
  • C-Reactive Protein / metabolism
  • Cells, Cultured
  • Chronic Disease
  • Fatigue / etiology*
  • Fatigue / physiopathology
  • Female
  • Humans
  • Hydrocortisone / pharmacology
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / blood
  • Interpersonal Relations
  • Lipopolysaccharides / pharmacology
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Severity of Illness Index
  • Stress, Psychological / complications*
  • Stress, Psychological / psychology


  • Anti-Inflammatory Agents
  • Biomarkers
  • Interleukin-6
  • Lipopolysaccharides
  • C-Reactive Protein
  • Hydrocortisone