Enhanced glucocorticoid sensitivity of cytokine release from circulating leukocytes stimulated with lipopolysaccharide in healthy male smokers

Abstract

Smoking is a strong cardiovascular risk factor that promotes inflammation. The source of elevated pro-inflammatory cytokines in the circulation of smokers is not fully understood. We investigated the release of pro-inflammatory cytokines from circulating leukocytes stimulated with lipopolysaccharide (LPS) and its inhibition by glucocorticoids in smokers and non-smokers. Ninety-three middle-aged apparently healthy men were categorized as smokers (>10 cigarettes/day; n=41) or life-long non-smokers ( n=52). Peripheral cortisol was assessed from overnight urine. C-reactive protein (CRP) and tumor necrosis factor (TNF)-α were measured in plasma. LPS-stimulated interleukin (IL)-6 and TNF-α release from harvested circulating leukocytes were assessed using an in vitro whole blood assay with and without co-incubation of increasing concentrations of either dexamethasone or hydrocortisone. Glucocorticoid sensitivity was defined as the concentration of glucocorticoids required that inhibits LPS-stimulated cytokine release by 50%. Smokers had higher CRP levels ( p=.005) and a trend for higher basal TNF-α levels ( p<.07), and they also showed lower IL-6 and TNF-α release after LPS-stimulation than non-smokers ( p’s < .001). While peripheral cortisol concentration showed no significant group difference, inhibition of LPS-stimulated leukocyte IL-6 and TNF-α release by either glucocorticoid was enhanced in smokers as compared to non-smokers ( p’s < .022). The finding suggests that, in spite of a low-grade systemic inflammation, smokers have decreased LPS-stimulated cytokine release from circulating leukocytes and greater glucocorticoid sensitivity of this cytokine release than non-smokers. Circulating leukocytes unlikely contribute to the elevated pro-inflammatory cytokine levels in the blood of smokers.