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Reduced Glucocorticoid Sensitivity of Monocyte Interleukin-6 Production in Male Industrial Employees who are Vitally Exhausted

From Department of Behavioral Sciences, Swiss Federal Institute of Technology (P.H.W., R.v.K., P.S., K.F., J.E.F.), Zurich; Department of Clinical Psychology II, University of Zurich (U. E.), Zurich, Switzerland

Address reprint requests to: Joachim E. Fischer, MD, MSc, Department of Behavioral Sciences, Swiss Federal Institute of Technology, Turnerstrasse 1, CH-8092 Zurich, Switzerland. Email: fischer{at}ifv.gess.ethz.ch

Received for publication April 26, 2002; revision received September 30, 2002

OBJECTIVE: Proinflammatory changes are thought to link vital exhaustion with adverse cardiovascular outcomes. Monocytes play a central role in the pathogenesis of atherosclerotic lesions and are a major source of circulating cytokines. We hypothesized that vital exhaustion may alter the regulation of monocyte activity, as measured by lipopolysaccharide (LPS)-stimulated and glucocorticoid inhibited release of the proinflammatory cytokine interleukin-6 (IL-6).

METHODS: In 166 middle-aged apparently healthy men, vital exhaustion was measured by the Shortened Maastricht Exhaustion Questionnaire. Subjects in the highest quartile (highly exhausted, N= 38) were compared with those in the second and third quartiles (moderately exhausted N= 89) vs. those in the lowest quartile (nonexhausted, N= 39) in terms of plasma C-reactive protein (CRP) and tumor necrosis factor- (TNF-) levels, and as to IL-6 release after LPS stimulation in vitro. Inhibition of IL-6 release was determined by coincubation with increasing concentrations of dexamethasone. Monocyte glucocorticoid sensitivity was defined as the dexamethasone concentration inhibiting IL-6 release by 50%.

RESULTS: Highly exhausted individuals had higher CRP levels than nonexhausted subjects (p= .008). LPS-stimulated IL-6 release was not significantly different between groups. However, in highly exhausted participants, dexamethasone was less able to inhibit IL-6 release (p= .010), and the glucocorticoid sensitivity was lower (p= .003) than in nonexhausted subjects.

CONCLUSIONS: In highly exhausted individuals, glucocorticoids exert less suppressive action on monocyte IL-6 release than in nonexhausted subjects. This finding points to altered regulation of monocyte cytokine production as one possible pathway linking exhaustion with atherosclerosis.

Key Words: Vital exhaustion, • coronary artery disease, • glucocorticoid sensitivity, • monocytes, • cytokines, • interleukin-6

Abbreviations: ANOVA = analysis of variance;; CRP = C-reactive protein;; GR = glucocorticoid receptor;; IL-6 = interleukin-6;; LPS = lipopolysaccharide;; TNF- = tumor necrosis factor-.

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