Pretreatment with stress cortisol enhances the human systemic inflammatory response to bacterial endotoxin

Abstract

Objective-There is continuing controversy regarding the effect of glucocorticoids on a systemic inflammatory process. Based on a model of glucocorticoid action that includes both pro-and antiinflammatory effects, we used the human experimental endotoxemia model to test the hypothesis that a transient elevation of plasma cortisol to stress-associated levels would enhance a subsequent (delayed) systemic inflammatory response to bacterial endotoxin. Design-Prospective, randomized, double-blind, placebo-controlled clinical investigation.Setting-Academic medical center. Subjects-Thirty-six healthy human volunteers.Interventions-Participants were randomized to receive a 6-hr intravenous infusion of saline (control), an intermediate dose of cortisol (Cort80; 6.3 mg/hr/70 kg), or a high dose of cortisol (Cort160; 12.6 mg/hr/70 kg) on day 1. On day 2, participants received an intravenous injection of 2 ng/kg Escherichia coli endotoxin followed by serial measurements of plasma cytokine concentrations.Measurements and Main Results-Baseline participant characteristics and cortisol and cytokine concentrations were similar in all three groups. The plasma cortisol response to endotoxemia on day 2 was similar in all three groups. The interleukin-6 response to endotoxemia was significantly increased in the Cort80 Group compared with the control Group (p = .004), whereas the interleukin-10 response was significantly suppressed (p = .034). Corresponding results for the Cort160 Group were not significantly different from control Group values.Conclusions-In this study, transient elevation of in vivo cortisol concentrations to levels that are observed during major systemic stress enhanced a subsequent, delayed in vivo inflammatory response to endotoxin. This appeared to be a dose-dependent effect that was more prominent at intermediate concentrations of cortisol than at higher concentrations of cortisol. Glucocorticoids (GCs) have been widely used to suppress inflammation since 1949 when Hench et al first described the anti-inflammatory effect of GCs in humans (1). Over the ensuing 50 years, most GC research focused on the anti-inflammatory and immune-suppressive properties of GCs, whereas comparatively little research examined the stimulatory properties of GCs that were, in fact, widely acknowledged before 1949 (2-4). More recently, investigators have again examined the stimulatory effects of GCs on inflammatory processes (5). Recent work has shown that GCs induce increased expression of receptors for inflammatory cytokines, including interleukin (IL)-1 (6), IL-2 (7), IL-4 (8), IL-6 (9), IL-7 (10) and interferon-γ (11) as well as granulocyte-macrophage colony-stimulating factor (12). GCs also stimulate effector cell functions, including phagocytosis by monocytes (13) and neutrophils (14), proliferative responses of T-cells (7) and macrophages (15), and tissue inflammatory responses to injury (16). NIH Public AccessTo account for both suppressive and stimulatory effects of GCs on inflammatory processes, a model of GC action ...

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