title: Suppression of human monocyte tumour necrosis factor-alpha release by glucocorticoid therapy: relationship to systemic monocytopaenia and cortisol suppression.
abstract: OBJECTIVE
  Glucocorticoids suppress the release of tumour necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha by autologous blood monocytes to 27% of pre-dose control. Plasma collected at intervals over the 48 h from dosing also suppressed monocyte TNF-alpha 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-alpha suppression was observed when prednisolone was added to blood samples collected from the volunteers when they were drug-free.
  
  
  CONCLUSIONS
  Blood concentration of prednisolone achieved after a dose of 1.5 mg kg-1 are sufficient to suppress monocyte TNF-alpha release and cause a biphasic change in peripheral blood monocyte numbers. Suppression of TNF-alpha is principally a direct glucocorticoid effect, rather than a consequence of other prednisolone-induced changes to blood composition.
authors.affiliation: Department of Pharmacology, University of Western Australia, Nedlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Steer
authors.forename: Q
authors.initials: Q
authors.lastname: Vuong
authors.forename: D A
authors.initials: DA
authors.lastname: Joyce
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000097:blood*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011239:Prednisolone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone; D006854:Hydrocortisone