Cytokine Inhibition after Glucocorticoid Exposure in Healthy Men with Low versus High Basal Cortisol Levels

Abstract

Objective: The balance between glucocorticoid (GC) release and GC sensitivity in target cells is believed to be important to maintain homeostasis in the neuroendocrine control of inflammation. We investigated the impact of in vivo exposure to adrenocorticotropic hormone (ACTH) and dexamethasone (DEX) on GC sensitivity measured in vitro in healthy individuals with high versus low baseline cortisol levels. Methods:136 healthy male volunteers were screened twice and sorted according to their 24-hour urinary free cortisol (UFC) excretion. The 10 individuals with the highest UFC (290 ± 87 nmol/24 h) and the 10 with the lowest UFC (168 ± 34 nmol/24 h) were further tested. Measurements were performed at baseline, after a low dose (0.5 μg/1.73 m²) of ACTH challenge and after 2 weeks’ exposure to DEX (0.1 mg twice daily). GC sensitivity was assessed in vitro as the ability of DEX to inhibit lipopolysaccharide-stimulated production of the cytokines interleukin 1-β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in a whole-blood assay. Results:After exposure to DEX in vivo, inhibition of IL-6 and TNF-α decreased. Also, after DEX in vivo, low-cortisol men showed lower inhibition of IL-1β and IL-6, both compared to the high-cortisol group and their own baseline levels. Conclusion: A downregulation of GC sensitivity in leukocytes after exposure to an exogenous GC seems to occur most strongly in men with low cortisol levels.

Further characterization of human glucocorticoid receptor mutants, R477H and G679S, associated with primary generalized glucocorticoid resistance

“…Lekander and co-workers reported low cortisol individuals defined as above, to display a weaker inhibition of IL-6 after a low dose Dexamethasone treatment compared to high cortisol individuals, thus being more sensitive to prolonged glucocorticoid exposure [186]. These results are in accordance to our findings described in paper IV.…”

Modulation of cortisol responses to the DEX/CRH test by polymorphisms of the interleukin-1beta gene in healthy adults

“…Previous studies showed that administration of DEX inhibited lipopolysaccharide (LPS)-stiumulated production of IL-1β [55,56], suggesting that DEX may affect the function of IL-1β gene. Therefore, future studies should examine the influence of IL-1β gene polymorphisms on not only basal IL-1β levels but also DEX-induced IL-1β levels.…”

Glucocorticoids regulate natural killer cell function epigenetically

“…In human volunteers, a 2 week administration of dexamethasone (a synthetic GC) resulted in an attenuation of GC mediated inhibition of IL-6 and TNF-alpha production in vitro [39]. Further, experimentally increased plasma cortisol levels (concentrations of 75 to 85 µg/dL for a 6-hr period) ending 12–144 hours before injection of endotoxin, resulted in an increased proinflammatory response to the bacterial product[13].…”