Inescapable shock induces resistance to the effects of dexamethasone

O’Connor, Kevin; Johnson, John D.; Hammack, Sayamwong E.; Brooks, Leah; Spencer, Robert L.; Watkins, Linda R.; Maier, Steven F.

doi:10.1016/s0306-4530(02)00035-5

Cited by 60 publications

(50 citation statements)

References 55 publications

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“…This suggests that cytokines interact with ACTH to mediate the inflammatory response at the level of the adrenal SRN. Although it has been shown that a severe stressor can increase cytokine levels in the brain and pituitary even in the absence of inflammation (44), and that ACTH can increase cytokine secretion in the adrenal gland in vitro (45, 46), we did not see such an increase in the level of adrenal cytokines following a high-ACTH stimulation alone.…”

Section: Il-6contrasting

confidence: 91%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress. T he hypothalamic-pituitary-adrenal (HPA) axis is a stressresponsive neuroendocrine system that controls circulating levels of the vital glucocorticoid (CORT) hormones corticosterone (in rodents) and cortisol (in humans). These are steroids synthesized by the adrenal gland in response to stimulation by adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary in response to corticotrophin-releasing hormone (CRH) and arginine vasopressin released from hypothalamic paraventricular neurons. These neurons receive circadian inputs from the suprachiasmatic nucleus and are activated in response to stress. Via the bloodstream, CORT accesses target tissues where it mediates metabolic, cognitive, and immune responses. CORT also regulates its own production through negative feedback inhibition of ACTH and CRH secretion from the pituitary and hypothalamus, respectively. To mount an effective response to stress, CORT must be secreted rapidly by the adrenal glands. However, because of its lipophilic nature, CORT cannot be prestored in vesicles and must therefore be rapidly synthesized de novo in response to ACTH stimulation.Under basal, unstressed conditions, ACTH and CORT exhibit ultradian oscillations. Although there is some evidence for pulsatility of CRH (1, 2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary-adrenal system (3, 4). The amplitude of these pulses varies in a circadian manner with larger pulses occurring at the start of the active phase (morning in humans, evening in rodents). Under normal physiological conditions, CORT secretion is tightly correlated with ACTH (5). However, there are a number of conditions where a dynamic dissociation between these hormones occurs (reviewed in ref. 6). For example, there is evidence that proinflammatory cytokines released during inflammation can poten...

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Section: Il-6contrasting

confidence: 91%

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Glucocorticoids are immunosuppressive, thereby providing a homeostatic regulation of the pro-inflammatory response. With prolonged stress, resistance to the effects of chronically elevated glucocorticoids leads to increased pro-inflammatory response to subsequent stress (O'Connor et al, 2003). This is consistent with findings from patients with multiple sclerosis where chronic stress leads to increased immune activation as evidenced by brain lesions, whereas acute stress leads to no such increase (Mohr & Pelletier, 2005).…”

Section: (Socrates 400 Bce)supporting

confidence: 88%

“…Whereas acute stress is likely to lead to an activation of a pro-inflammatory response, this response will culminate in hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid production (O'Connor et al, 2003;Webster et al, 2002). Glucocorticoids are immunosuppressive, thereby providing a homeostatic regulation of the pro-inflammatory response.…”

Section: (Socrates 400 Bce)mentioning

confidence: 99%

Reciprocal Communication between the Nervous and Immune Systems: Crosstalk, Back-talk and Motivational Speeches

Kaplin

Bartner

2005

International Review of Psychiatry

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“…Severe stress, as a result of repeated or persistent exposure to behavioral or psychological challenges, has been shown to impair the anti-inflammatory capacities of GC hormones (Johnson et al, 2004;O'Connor et al, 2003a;Quan et al, 2001;Reber et al, 2006;Sheridan et al, 2000). Previous studies have demonstrated that repeated social stress in mice is associated with decreased GC sensitivity of immune cells and excessive inflammation Engler et al, 2005;Johnson et al, 2004;Merlot et al, 2004;Sonoda et al, 2005;Stark et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

Engler

Bailey

Engler

et al. 2008

Psychoneuroendocrinology

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SummaryFrequent or chronic stress as a result of repeated or persistent exposure to social challenges has been shown to affect the glucocorticoid (GC) responsiveness of immune cells in mice. Lipopolysaccharide-stimulated splenocytes of mice that were repeatedly subjected to social disruption were less sensitive to the anti-inflammatory actions of GC as evident from an increased production of pro-inflammatory cytokines and enhanced cell survival. The development of functional GC resistance was accompanied by the accumulation of GC-insensitive CD11b + cells in the spleen. These cells were shown to exhibit impaired nuclear translocation of the GC receptor and lack of GCinduced suppression of NF-κB. Similar impairments in GC receptor function have been reported after in vitro treatment of various cell lines with interleukin (IL)-1. The aim of this study was to elucidate whether IL-1 is a critical factor for the development of GC resistance in socially stressed mice. In the first experiment, we investigated if repeated social stress alters plasma levels and tissue gene expression of IL-1α and IL-1β. It revealed that recurrent stressor exposure significantly increased splenic and hepatic mRNA expression and the plasma protein level of IL-1β, and hepatic mRNA expression of IL-1α. In the second experiment, IL-1 receptor type 1 (IL1R1)-deficient mice were subjected to the stressor and both the tissue distribution of CD11b + cells and the GC sensitivity of the splenocytes were compared to wildtype mice. Mice lacking the IL1R1 exhibited adrenal hypertrophy, thymic involution, and elevated serum corticosterone levels in response to the stressor but did not show splenic accumulation of CD11b + cells and failed to develop GC resistance. These findings suggest that IL-1 plays a critical role in the development of the social stress-associated GC resistance in the murine spleen.

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Inescapable shock induces resistance to the effects of dexamethasone

Cited by 60 publications

References 55 publications

Dynamic responses of the adrenal steroidogenic regulatory network

Dynamic responses of the adrenal steroidogenic regulatory network

Reciprocal Communication between the Nervous and Immune Systems: Crosstalk, Back-talk and Motivational Speeches

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

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