Down regulation of hepatic glucocorticoid receptors after endotoxin treatment

Abstract

The mechanism by which endotoxin administration results in hypoglycemia was evaluated by characterizing [3H]dexamethasone binding and phosphoenolpyruvate carboxykinase activity in hepatic cytosol preparations from treated and control mice. Starved mice were given Escherichia coli 0111:B4 endotoxin or saline intraperitoneally on day 3 after bilateral adrenalectomy. [3H]dexamethasone binding was measured by the charcoal method after the incubation of cytosol preparations with [3H]dexamethasone in the presence or absence of unlabeled dexamethasone. Changes in [3H]dexamethasone binding were found to be time and dose dependent in treated mice. When mice given different doses of endotoxin reached the same stage of morbidity, as indicated by the average time of death, significantly lower glucocorticoid binding was measured. Scatchard analysis of binding isotherms defined a. single class of binding sites. Association and dissociation rate constants and the equilibrium dissociation constant (Kd) were not altered, but the maximum number of binding sites was depressed by endotoxin. The rank order of potency of competitors for [3H]dexamethasone binding, dexamethasone, > hydrocortisone = corticosterone > deoxycorticosterone > progesterone > testosterone = estradiol, was consistent with a glucocorticoid receptor, although the competition was not altered by endotoxin. Endotoxin treatment prevented the glucocorticoid-induced increase in hepatic phosphoenolpyruvate carboxykinase activity. We conclude that the hypoglycemia of endotoxin poisoning is effected, in part, by the inhibition of the glucocorticoid-mediated induction of phosphoenolpyruvate carboxykinase via the down regulation of hepatic glucocorticoid receptors.

Decreased glucocorticoid receptor expression during critical illness

“…Most endotoxin-induced and lipopolysaccharide (LPS) injury models have demonstrated decreased ligand affinity and down-regulation of GCR-α expression. [25][26][27][28][29][30][31][32][33][34] There are some animals model of sepsis, however, which have demonstrated down-regulation of GCR-α or decreased ligand affinity and induction of GCR-β expression. 35,36 In the last years, data on GCR expression and critical illness in humans have started evolving and many groups have described glucocorticoid resistance in cohorts of septic patients.…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…In a human cell line, activation of NF-κB by TNF-α had a direct doseand time-dependent effect on GR levels with a disproportionate increase in GRβ over GRα (123). Experimental sepsis is associated with decreased GRα transcription in circulating cells (124), heart (125), lymph node-spleen (124), liver (125)(126)(127), kidney (127), lung tissue (125)(126)(127)(128)(129), and skeletal muscle (125). Moreover, the endothelial GRα is required for protection against sepsis (see section Endothelium) (130).…”

Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone

“…Another mechanism of GR action is currently thought to be important for most of the GR anti-inflammatory functions, which is based on the ability of liganded GR monomers to interact directly with other proinflammatory transcription factors, such as NF-B, thereby repressing or potentiating their activity (17). GR gene transcription may be crucially changed after induction of sepsis, although conflicting results have been reported concerning the effect of sepsis on GR expression (29,49,52,53,54). Therefore, the first aim of the present study was to investigate the effect of high-dose corticosteroid therapy on GR expression in septic guinea pig lungs using immunohistochemistry, Western blotting, and RT-PCR analyses.…”