Cortisol is a prototypical human stress hormone essential for life, yet the precise role of cortisol in the human stress response to injury or infection is still uncertain. Glucocorticoids (GCs) such as cortisol are widely understood to suppress inflammation and immunity. However, recent research shows that GCs also induce delayed immune effects manifesting as immune stimulation. In this study, we show that cortisol enhances the immune-stimulating effects of a prototypical proinflammatory cytokine, interferon-υ (IFN-υ). We tested the hypothesis that cortisol enhances IFN-υ–mediated proinflammatory responses of human mononuclear phagocytes (monocyte/macrophages [MOs]) stimulated by bacterial endotoxin (lipopolysaccharide [LPS]).
Human MOs were cultured for 18 hours with or without IFN-υ and/or cortisol before LPS stimulation. MO differentiation factors granulocyte-macrophage colony stimulating factor (GM-CSF) or M-CSF were added to separate cultures. We also compared the inflammatory response with an acute, 4-hour MO incubation with IFN-υ plus cortisol and LPS to a delayed 18-hour incubation with cortisol before LPS exposure. MO activation was assessed by interleukin-6 (IL-6) release and by multiplex analysis of pro- and anti-inflammatory soluble mediators.
After the 18-hour incubation, we observed that cortisol significantly increased LPS-stimulated IL-6 release from IFN-υ–treated undifferentiated MOs. In GM-CSF–pretreated MOs, cortisol increased IFN-υ–mediated IL-6 release by >4-fold and release of the immune stimulant IFN-α2 (IFN-α2) by >3-fold, while suppressing release of the anti-inflammatory mediator, IL-1 receptor antagonist to 15% of control. These results were reversed by either the GC receptor antagonist RU486 or by an IFN-υ receptor type 1 antibody antagonist. Cortisol alone increased expression of the IFN-υ receptor type 1 on undifferentiated and GM-CSF–treated MOs. In contrast, an acute 4-hour incubation of MOs with IFN-υ and cortisol showed classic suppression of the IL-6 response to LPS.
These results reveal a surprisingly robust proinflammatory interaction between the human stress response hormone cortisol and the immune activating cytokine IFN-υ. The results support an emerging physiological model with an adaptive role for cortisol, wherein acute release of cortisol suppresses early proinflammatory responses but also primes immune cells for an augmented response to a subsequent immune challenge. These findings have broad clinical implications and provide an experimental framework to examine individual differences, mechanisms, and translational implications of cortisol-enhanced immune responses in humans.
From the *Department of Anesthesiology and Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
†Independent Researcher, Enfield, New Hampshire
‡Department of Anesthesiology and Orthopedics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
§Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
Accepted for publication April 19, 2018.
Funding: This study was supported by the Centers of Biomedical Research Excellence (COBRE) grant # P20 RR 016437 and National Institutes of Health grant # RO1AI051547. Flow Cytometry and Luminex Assays were performed in DartLab, the Immune Monitoring and Flow Cytometry Shared Resource, supported by a National Cancer Institute Cancer Center support grant to the Norris Cotton Cancer Center (P30CA023108-37), and an Immunology COBRE Grant (P30GM103415-15) from the National Institute of General Medical Sciences.
The authors declare no conflicts of interest.
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Address correspondence to Mark P. Yeager, MD, Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756. Address e-mail to email@example.com.