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Absence of glucocorticoids augments stress-induced Mkp1 mRNA expression within the hypothalamic-pituitary-adrenal axis.

ABSTRACT: Stress-induced activation of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons trigger CRH release and synthesis. Recent findings have suggested that this process depends on the intracellular activation (phosphorylation) of ERK1/2 within CRH neurons. We have recently shown that the presence of glucocorticoids constrains stress-stimulated phosphorylation of PVN ERK1/2. In some peripheral cell types, dephosphorylation of ERK has been shown to be promoted by direct glucocorticoid upregulation of the MAP kinase phosphatase 1 (Mkp1) gene. In this study, we tested the hypothesis that glucocorticoids regulate Mkp1 mRNA expression in the neural forebrain (medial prefrontal cortex, mPFC, and PVN) and endocrine tissue (anterior pituitary) by subjecting young adult male Sprague-Dawley rats to various glucocorticoid manipulations with or without acute psychological stress (restraint). Restraint led to a rapid increase in Mkp1 mRNA within the mPFC, PVN, and anterior pituitary, and this increase did not require glucocorticoid activity. In contrast to glucocorticoid upregulation of Mkp1 gene expression in the peripheral tissues, we found that the absence of glucocorticoids (as a result of adrenalectomy) augmented basal mPFC and stress-induced PVN and anterior pituitary Mkp1 gene expression. Taken together, this study indicates that the presence of glucocorticoids may constrain Mkp1 gene expression in the neural forebrain and endocrine tissues. This possible constraint may be an indirect consequence of the inhibitory influence of glucocorticoids on stress-induced activation of ERK1/2, a known upstream positive regulator of Mkp1 gene transcription.

SUBMITTER: Osterlund CD

PROVIDER: S-EPMC3869093 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Absence of glucocorticoids augments stress-induced Mkp1 mRNA expression within the hypothalamic-pituitary-adrenal axis.

Osterlund Chad D CD Thompson Vanessa V Hinds Laura L Spencer Robert L RL

The Journal of endocrinology 20131128 1

Stress-induced activation of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons trigger CRH release and synthesis. Recent findings have suggested that this process depends on the intracellular activation (phosphorylation) of ERK1/2 within CRH neurons. We have recently shown that the presence of glucocorticoids constrains stress-stimulated phosphorylation of PVN ERK1/2. In some peripheral cell types, dephosphorylation of ERK has been shown to be promoted by d ...[more]

PMID: 24287620

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Project description:Natural glucocorticoids, a class of cholesterol-derived hormones, modulate an array of metabolic, anti-inflammatory, immunosuppressive and cognitive signaling. The synthesis of natural glucocorticoids, largely cortisol in humans, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and exhibits pronounced circadian variation. Considering the central regulatory function of endogenous glucocorticoids, maintenance of the circadian activity of the HPA axis is essential to host survival and chronic disruption of such activity leads to systemic complications. There is a great deal of interest in synthetic glucocorticoids due to the immunosuppressive and anti-inflammatory properties and the development of novel dosing regimens that can minimize the disruption of endogenous activity, while still maintaining the pharmacological benefits of long-term synthetic glucocorticoid therapy. Synthetic glucocorticoids are associated with an increased risk of developing the pathological disorders related to chronic suppression of cortisol rhythmicity as a result of the potent negative feedback by synthetic glucocorticoids on the HPA axis precursors. In this study, a mathematical model was developed to explore the influence of chronopharmacological dosing of exogenous glucocorticoids on the endogenous cortisol rhythm considering intra-venous and oral dosing. Chronic daily dosing resulted in modification of the circadian rhythmicity of endogenous cortisol with the amplitude and acrophase of the altered rhythm dependent on the administration time. Simulations revealed that the circadian features of the endogenous cortisol rhythm can be preserved by proper timing of administration. The response following a single dose was not indicative of the response following long-term, repeated chronopharmacological dosing of synthetic glucocorticoids. Furthermore, simulations revealed the inductive influence of long-term treatment was only associated with low to moderate doses, while high doses generally led to suppression of endogenous activity regardless of the chronopharmacological dose. Finally, chronic daily dosing was found to alter the responsiveness of the HPA axis, such that a decrease in the amplitude of the cortisol rhythm resulted in a partial loss in the time-of-day dependent response to CRH stimulation, while an increase in the amplitude was associated with a more pronounced time-of-day dependence of the response.

Dataset Information

Absence of glucocorticoids augments stress-induced Mkp1 mRNA expression within the hypothalamic-pituitary-adrenal axis.

Publications

Absence of glucocorticoids augments stress-induced Mkp1 mRNA expression within the hypothalamic-pituitary-adrenal axis.

Similar Datasets

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