Suppression of human monocyte tumour necrosisfactor-alpharelease by glucocorticoid therapy: relationshipto systemic monocytopaenia and cortisol suppression

Abstract

Aims Glucocorticoids suppress the release of tumour necrosis factor-a (TNF-a) 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-a 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 lipopolysaccharideinduced TNF-a 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-a by autologous blood monocytes to 27% of pre-dose control. Plasma collected at intervals over the 48 h from dosing also suppressed monocyte TNF-a 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-a 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-a release and cause a biphasic change in peripheral blood monocyte numbers. Suppression of TNF-a is principally a direct glucocorticoid effect, rather than a consequence of other prednisoloneinduced changes to blood composition.

Concomitant Endocrine and Immune Alterations during Alcohol Intoxication and Acute Withdrawal in Alcohol-Dependent Subjects

“…Removal of cortisol hypersecretion via acute alcohol withdrawal may have produced elevated numbers of monocytes. Indeed, this position is supported by data demonstrating that glucocorticoid therapy reduces monocyte numbers and function in human peripheral blood, while cessation of therapy produces monocytosis [26]. Nevertheless, as the small sample size did not produce statistically significant associations between cortisol levels and monocyte numbers, further research is required to test this position.…”

Comprehensive Immunohistochemical Studies on Canine Necrotizing Meningoencephalitis (NME), Necrotizing Leukoencephalitis (NLE), and Granulomatous Meningoencephalomyelitis (GME)

“…Corticosteroids such as dexamethasone and prednisone inhibit T cellor macrophage-mediated immunity, production of cytokines, and partial B cell-mediated immunity. 6,10,11,22,33,40,50 This study was performed with the cases that progressed acutely or chronically despite continuous treatment and maintenance. Certainly, some degree of inflammatory reactions could have been affected by corticosteroids.…”

Interpreting Stress Responses during Routine Toxicity Studies

“…In contrast, monocyte counts decrease during infusion of cortisol in humans; the pattern of decrease parallels that of lymphocytes (Calvano et al 1987). Dosing of humans with synthetic glucocorticoids results in decreases in monocyte counts, sometimes followed by sustained increases in the face of continued dosing (Rinehart et al 1975;Steer, Vuong, and Joyce 1997). Decreased monocyte counts may be caused by decreased production, as sustained exposure to glucocorticoids results in decreased generation and release of monocytes from bone marrow in mice (Thompson and van Furth 1973).…”