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 ona model of glucocorticoid action that includes both pro- and anti-inflammatory 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.

Trial registration: ClinicalTrials.gov NCT00396344.

Conflict of interest statement

The authors have not disclosed any potential conflicts of interest.

Figures

Figure 1

Total plasma cortisol immediately before (8:00 am) and 2 and 4 hrs after intravenous injection of Escherichia coli endotoxin (lipopolysaccharide), 2 ng/kg. Participants had been treated the day before with a 6-hr infusion of intravenous saline (control), 1.5 µg/kg/min hydrocortisone (Cort80), or 3.0 µg/kg/min hydrocortisone (Cort160). Data presented as mean (se). LPS, lipopolysaccharide.

Figure 2

Plasma adrenocorticotrophic (ACTH) concentrations immediately before (8:00 am) and at 2, 3, and 4 hrs after intravenous injection of Escherichia coli endotoxin (lipopolysaccharide [LPS]), 2 ng/kg. Participants had been treated the day before with a 6-hr infusion of intravenous saline (control), 1.5 µg/kg/min hydrocortisone (Cort80), or 3.0 µg/ kg/min hydrocortisone (Cort160). **p <.01 Cort80 versus control; ## p < .01 Cort80 vs. Cort160. Data presented as mean (se).

Figure 3

Plasma interleukin (IL)-6 concentrations measured immediately before and at 2, 3, 4, and 8 hrs after intravenous injection of Escherichia coli endotoxin (lipopolysaccharide [LPS]), 2 ng/kg. Participants had been treated the day before with a 6-hr infusion of intravenous saline (control), 1.5 µg/kg/min hydrocortisone (Cort80), or 3.0 µg/kg/min hydrocortisone (Cort160). The plasma IL-6 response was significantly greater in the Cort80 group compared with the control group (p = .004). +p < .05 Cort80 vs. control; **p < .01 Cort160 vs. control; ***p < 0.001 Cort80 vs. control. Data presented as mean (se).

Figure 4

Plasma interleukin (IL)-10 concentrations measured immediately before and at 2, 3, 4, and 8 hrs after intravenous injection of Escherichia coli endotoxin (lipopolysaccharide [LPS]), 2 ng/kg. Participants had been treated the day before with a 6-hr infusion of intravenous saline (control), 1.5 µg/kg/min hydrocortisone (Cort80), or 3.0 µg/kg/min hydrocortisone (Cort160). The plasma IL-10 response was significantly lower in the Cort80 group compared with the control group (p = .034). +p < .05 Cort80 vs. control. Data presented as mean (se).

Figure 5

Plasma tumor necrosis factor (TNF)-α concentrations measured immediately before and at 2, 3, 4, and 8 hrs after intravenous injection of Escherichia coli endotoxin (lipopolysaccharide), 2 ng/kg. Participants had been treated the day before with a 6-hr infusion of intravenous saline (control), 1.5 µg/kg/min hydrocortisone (Cort80), or 3.0 µg/ kg/min hydrocortisone (Cort160). There were no significant differences in TNF-α response between groups.