Suppression of human monocyte tumour necrosis factor-α release by glucocorticoid therapy: relationship to systemic monocytopaenia and cortisol suppression

Abstract

Aims Glucocorticoids suppress the release of tumour necrosis factor-α (TNF-α) by macrophages in vitro and cause monocytopaenia in vivo. These actions may contribute to anti-inflammatory and immunosuppressant effects. We therefore examined relationships between prednisolone concentration, suppression of monocyte TNF-α release, monocytopaenia and suppression of total cortisol concentration in healthy volunteers treated with a single dose (1.5 mg kg⁻¹ ) of the glucocorticoid, prednisolone.

Methods Monocyte numbers, total cortisol concentration and prednisolone concentration were measured in blood samples collected over 48 h after the dose. Plasma from these samples was also tested for its capacity to suppress lipopolysaccharide-induced TNF-α release from monocytes in autologous whole blood cultures.

Results At 4 h after the dose, monocyte numbers in peripheral blood had fallen to a mean of 18% of the pre-dose level whilst plasma total cortisol had fallen to 9% of the pre-dose concentration. Monocyte numbers recovered in concordance with elimination of prednisolone and there was a significant relative monocytosis at 24 h. The recovery of plasma cortisol was delayed in comparison, with cortisol remaining significantly suppressed at 24 h. Plasma samples taken at 2 h after the dose (corresponding to peak plasma prednisolone concentration) suppressed the lipopolysaccharide-stimulated production of TNF-α by autologous blood monocytes to 27% of pre-dose control. Plasma collected at intervals over the 48 h from dosing also suppressed monocyte TNF-α release in relation to the prednisolone concentration therein. Suppression was largely reversed by the glucocorticoid antagonist, mifepristone. A similar relationship between prednisolone concentration and TNF-α suppression was observed when prednisolone was added to blood samples collected from the volunteers when they were drug-free.

Conclusions Blood concentrations of prednisolone achieved after a dose of 1.5 mg kg⁻¹ are sufficient to suppress monocyte TNF-α release and cause a biphasic change in peripheral blood monocyte numbers. Suppression of TNF-α is principally a direct glucocorticoid effect, rather than a consequence of other prednisolone-induced changes to blood composition.

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