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Suppression of human monocyte tumour necrosisfactor‐ α release by glucocorticoid therapy: relationshipto systemic monocytopaenia and cortisol suppression
Author(s) -
Steer James H.,
Vuong Quylinh,
Joyce David A.
Publication year - 1997
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1997.00586.x
Subject(s) - prednisolone , endocrinology , monocyte , medicine , glucocorticoid , tumor necrosis factor alpha , lipopolysaccharide , hydrocortisone , proinflammatory cytokine , chemistry , inflammation
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.