Abstract
Corticosterone (CORT), a critical mediator of the hypothalamus pituitary adrenal axis in rodents, is a stress hormone that is classically viewed as possessing immune-suppressive properties. CORT is now appreciated to also mediate the neuroimmune-priming effect of stress to innate-immune stimulation, and hence serves as a mechanistic link to the neuroimmune involvement in stress-related disorders. However, these dichotomous actions of CORT remain poorly defined. This study investigated the conditions and concentration dependency of CORT’s actions required to prime the innate-immune system. Here, we measured the effect of CORT pretreatment on the downstream pro-inflammatory responses of BV2 mouse microglia-like cells stimulated by lipopolysaccharide (LPS). We quantified the concentration-dependent CORT-mediated attenuation and enhancement of LPS-stimulated inflammatory response. A high physiological concentration (500 nM) of CORT attenuated LPS-induced inflammatory IL-1β cytokine production in a glucocorticoid receptor-dependent manner. However, a low concentration (50 nM) of CORT increased expression and release of IL-1β in a mineralocorticoid receptor-dependent manner, with accompanied increases in NF-κB translocation and changes to related gene transcription. These results suggest that a mild elevation in CORT may cause selective adaptations in microglia-like cells to overrespond to a second immune challenge in a non-classical manner, thus partially explaining both pro- and anti-inflammatory effects of CORT reported in the literature.
Highlights
Chronic Stress Can Be Pro-inflammatoryChronic psychological stress is associated with the development of psychosomatic disorders such as posttraumatic stress disorder and major depressive disorder [1, 2], as well as the exacerbation and persistence of neurological damage [3, 4]
Comparisons with vehicle reference group found that co-treatment of CORT with LPS was significantly inhibitory toward IL-1β release at 50 nM [mean difference= −60%, t(36) = −2.37, p < 0.05], 300 nM [mean difference= −69%, t(36) = −2.72, p < 0.05], and 1 μM [mean difference= −70%, t(36) = −2.76, p < 0.01]
Using specific antagonists to glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), the two CORTbinding receptors, this study has further demonstrated that this low concentration CORT priming of NF-κB translocation and IL-1β release is MR dependent, while high concentration CORT-induced suppression of IL-1β relies on GR binding
Summary
Chronic psychological stress is associated with the development of psychosomatic disorders such as posttraumatic stress disorder and major depressive disorder [1, 2], as well as the exacerbation and persistence of neurological damage [3, 4]. Chronic stress itself can result in increased pro-inflammatory innate-immune responses. Physically healthy soldiers with combat experience exhibited increased plasma C-reactive-protein (CRP), an acute-phase protein produced during inflammation, which further correlated with depressive and posttraumatic stress disorder assessment scores [2]. Meta-analyses have further uncovered a link between physiological stress-related depression and increases in pro-inflammatory factors such as CRP, IL-1, and IL-6, implicating an immune consequence of the physiological stress response [6, 7]
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