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PubMed2003

Inhibition of the stem cell factor-induced migration of mast cells by dexamethasone.

Mast cell accumulation can be causally related to several allergic inflammations. Previous work has demonstrated that glucocorticoids decreased tissue mast cell number, and stem cell factor (SCF)-induced migration of mast cells required p38 MAPK activation. In the present study we investigated the effects of dexamethasone on SCF-induced migration of rat peritoneal mast cells (RPMCs). SCF significantly induced the migration of RPMCs at 4 h. Dexamethasone dose-dependently inhibited SCF-induced migration of RPMCs (approximately 90.1% at 100 nM; P < 0.05). The MAPK p38 inhibitor SB203580 (20 microM) also inhibited the SCF-induced migration. The ability of SCF to enhance morphological alteration and filamentous actin formation was also abolished by treatment with dexamethasone. Dexamethasone inhibited SCF-induced p38 MAPK activation to near-basal levels and induced MAPK phosphatase-1 expression. In addition, SCF-induced inflammatory cytokine production was significantly inhibited by treatment with dexamethasone or SB203580 (P < 0.01). Our results show that dexamethasone potently regulates SCF-induced migration, p38 MAPK activation, and inflammatory cytokine production through the expression of MKP-1 protein in RPMCs. Such modulation may have functional consequences during dexamethasone treatment, especially mast cell-mediated allergic inflammation disorders.

Actins↗
PubMed2006

Differential effects of maternal dexamethasone treatment on circulating thyroid hormone concentrations and tissue deiodinase activity in the pregnant ewe and fetus.

Clinically, treatment of pregnant women at risk of preterm delivery with synthetic glucocorticoids accelerates fetal maturation. This study investigated the effect of maternal dexamethasone treatment, in clinically relevant doses, on plasma thyroid hormone concentrations and tissue deiodinase activities (D1, D2, and D3) in ewes and their fetuses. From 125 d of gestation (term 145 +/- 2 d), pregnant ewes were injected twice im with either saline (2 ml of 0.9% NaCl, n = 11) or dexamethasone (2 x 12 mg in 2 ml of saline, n = 10) at 24-h intervals. Maternal dexamethasone treatment increased plasma T(3) and reverse T(3) (rT(3)), but not T(4), concentrations in the fetuses. In the dexamethasone-exposed fetuses, hepatic D1 activity was higher, and renal and placental D3 activities were lower, than in the saline-exposed fetuses. In the ewes, plasma concentrations of T(3) and T(4) were reduced, and rT(3) increased, by dexamethasone treatment without any change in tissue deiodinase activity. Therefore, maternal dexamethasone treatment has different effects on the thyroid hormone axis of the pregnant ewe and fetus. In the fetus, the dexamethasone-induced rise in circulating T(3) may be due to both increased hepatic production of T(3) from T(4), and reduced clearance of T(3) by the kidney and placenta. Changes in T(3) bioavailability may mediate some of the maturational effects of antenatal glucocorticoid treatment in the preterm fetus.

Animals↗
PubMed1981

Neonatal dexamethasone administration. II. Persistent alteration of circadian serum anterior pituitary hormone rhythms in rats.

Newborn male rats were treated SC with dexamethasone phosphate (100 microgram) or dexamethasone acetate (100 microgram) on postnatal day 1, dexamethasone phosphate (5.0 microgram) opn postnatal days 1, 2, 3, or the corresponding drug vehicle. All animals were sacrificed 65-70 days later at previously determined daily trough and peak times of serum LH, TSH, and corticosterone: 0700 and 0100 h for LH, 0700 and 1300 h for TSH, and 0700 and 1900 h for corticosterone. None of the three dexamethasone treatment regimens affected the circadian variation of serum LH or corticosterone. Dexamethasone phosphate (100 microgram) altered the normal circadian rhythm of serum TSH in the adult animals, but the other two dexamethasone treatments did not affect the TSH rhythm. Basal 0700 h serum levels of FSH, PRL, and GH were also measured in these animals; none of the dexamethasone treatments altered the levels of these hormones compared to levels in the vehicle-injected controls.

Animals↗
PubMed1984

Effect of dexamethasone on adenosine 3',5'-monophosphate content and phosphodiesterase activities in 3T3-L1 adipocytes.

After incubation with 0.5 mM isobutylmethylxanthine, 1 microM dexamethasone, and 1 microM insulin for 72 h, 3T3-L1 cells acquire the phenotypic characteristics of mature adipocytes, including a hormone-sensitive particulate cAMP phosphodiesterase activity. In addition, adipocytes contain soluble cAMP and calmodulin-sensitive and -insensitive cGMP phosphodiesterase activities. After exposure of the differentiated cells to 1 microM epinephrine, cAMP content increased, reaching a maximum in 2-4 min, and then declined to the control level by 20 min. After incubation of adipocytes with 10 nM dexamethasone for 72 h, the initial increment in cAMP produced by epinephrine was not altered, but the decline in cellular cAMP to basal levels was delayed. Treatment with 10 nM dexamethasone prevented hormonal activation of particulate cAMP phosphodiesterase activity without altering basal activity (11). Soluble cAMP and calmodulin-sensitive and -insensitive cGMP phosphodiesterase activities were also reduced by exposure to 10 nM dexamethasone; higher concentrations were required to decrease basal particulate phosphodiesterase activities. Estradiol did not alter phosphodiesterase activities. Incubation of either undifferentiated (fibroblasts) or differentiated (adipocytes) 3T3-L1 cells with 1 microM dexamethasone for 48 h reduced cAMP and cGMP phosphodiesterase activities. After removal of dexamethasone, phosphodiesterase activities were restored to control levels in 4-6 days. The effects of dexamethasone on phosphodiesterase activities could in part account for the observed alterations in hormone-induced accumulation of cAMP in steroid-treated cells and for the permissive effects of glucocorticoids on certain cAMP-mediated processes.

1-Methyl-3-isobutylxanthine↗
PubMed1986

The effects of 1,25-dihydroxyvitamin D3 and dexamethasone on rat osteoblast-like primary cell cultures: receptor occupancy and functional expression patterns for three different bioresponses.

The effects of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and dexamethasone to regulate collagen and osteocalcin synthesis and induction of 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase) activity were studied in rat osteoblast-like cell primary cultures. In this culture system, the basal levels of collagen and osteocalcin synthesis increased with rising cell density in culture. At maximal doses, both 1,25-(OH)2D3 (8.1 nM) and dexamethasone (130 nM) reduced collagen synthesis to about 50% of the control levels, 1,25-(OH)2D3 affected osteocalcin synthesis in a biphasic manner: stimulatory at low doses, which peaked near 0.33 nM to reach 3- to 5-fold the basal level, followed by a gradual return to the basal level at higher concentrations. Dexamethasone had only a slight stimulatory effect on osteocalcin. 1,25-(OH)2D3 also induced 24-hydroxylase activity in rat osteoblast-like cells, while dexamethasone had no effect on the enzyme. Induction of enzyme activity achieved a 4- to 6-fold rise, but required higher concentrations of 1,25-(OH)2D3 to achieve maximal levels (16 nM). The half-maximal doses (ED50) of 1,25-(OH)2D3 required for each bioresponse were different. The approximate ED50 for the inhibition of collagen synthesis was near the Kin (0.4 nM; apparent dissociation constant of receptor nuclear internalization), while the ED50 for osteocalcin synthesis (0.08 nM) was below the Kin, and the ED50 for 24-hydroxylase induction (20 nM) was greater than the Kin. The ED50 for dexamethasone on collagen synthesis (20 nM) was about 5-fold higher than the Kin (4 nM) of dexamethasone receptor binding. The potencies of various vitamin D3 metabolites in all three functional responses followed their abilities to compete for the 1,25-(OH)2D3 receptor, indicating that these actions were 1,25-(OH)2D3 receptor mediated. In summary, these studies explored bone cell bioresponses to 1,25-(OH)2D3 and dexamethasone and examined the relationship between receptor occupancy and functional expression. Each action exhibited a different dose-response pattern, implying that different levels of control are required for each individual response.

Animals↗
PubMed1986

Effect of dexamethasone on 25-hydroxyvitamin D3 metabolism by chick kidney cell cultures.

The ability of dexamethasone to alter the metabolism of [3H]25-hydroxyvitamin D3 ([3H]25OHD3) metabolism by primary cultures of chick kidney cells was tested. Dexamethasone, present for 24 or 48 h at 10(-8)-10(-6) M, decreased production of [3H]1,25-dihydroxyvitamin D3 to approximately 60% of control levels. If cultures were pretreated with 1,25-dihydroxyvitamin D3 to reduce 25OHD3-1-hydroxylase activity and induce 25OHD3-24-hydroxylase activity, no effect of dexamethasone on either of the enzymes was observed. When the substrate concentration was varied, analysis of the data revealed that dexamethasone decreases both the maximal velocity of the rate of 1-hydroxylation to 25OHD3 and the half-maximal substrate concentration for 25OHD3. Dexamethasone had no effect on the cell number of the cultures, as assessed by DNA content, but did reduce the total protein content to approximately 70% of control values. Dexamethasone did not alter the response of chick kidney cells to PTH in terms of cAMP production or the metabolism of 25OHD3. The results suggest that dexamethasone has the potential to alter 25OHD3 metabolism through a direct effect on the renal cell.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1991

Opposing effects of retinoic acid and dexamethasone on cellular retinol-binding protein ribonucleic acid levels in the rat.

Cellular retinol-binding protein (CRBP) is a potential mediator of vitamin A action. To determine whether retinoic acid and dexamethasone administration, alone and in combination, influence CRBP gene expression, adult female vitamin A-sufficient Sprague-Dawley rats randomly received 1) all-trans retinoic acid (100 micrograms) by intragastric intubation, 2) dexamethasone (2 micrograms/g BW) by ip injection, or 3) both all-trans retinoic acid and dexamethasone in the same doses. Control animals received either cottonseed oil by intragastric intubation or saline by ip injection. Six hours after treatment, lung and liver tissue were collected for Northern blot analysis with the radiolabeled cDNA specific for rat CRBP. Retinoic acid administration increased the amount of lung CRBP mRNA only, whereas dexamethasone decreased both lung and liver CRBP mRNA abundance. In animals treated with both retinoic acid and dexamethasone, CRBP mRNA abundance was also reduced. We conclude that CRBP gene expression can be modulated by both retinoic acid and dexamethasone in the vitamin A-sufficient animal. In the whole animal, our findings indicate that dexamethasone not only represses CRBP gene expression, but also opposes the effect of retinoic acid.

Animals↗
PubMed1975

Differences in corticosterone and dexamethasone binding to rat brain and pituitary.

In an attempt to relate binding of 3H-corticosterone and 3H-dexamethasone to their respective potencies in blocking pituitary-adrenal activity, cytosol binding in vitro and cell nuclear binding both in vivo and in tissue slices in vitro were studied in hippocampus, hypothalamus, and anterior pituitary of adrenalectomized rats. It was found that the extremely potent glucocorticoid dexamethasone has a different pattern of binding than corticosterone in the brain and in the anterior pituitary. 1) In cytosol, differences in the estimated binding capacities in a particular tissue for 3H-corticosterone and 3H-dexamethasone and different rates of inactivation in the ability to bind the two steroids are observed. 2) For 3H-corticosterone, cytosol binding in hippocampus is higher than that in hypothalamus, and cell nuclear binding follows the same pattern. For 3H-dexamethasone, cytosol binding is again higher in the hippocampus than in hypothalamus but cell nuclear binding in the two structures is not significantly different. With respect to the anterior pituitary, binding to cell nuclei is higher for 3H-dexamethasone, while the binding to cytosol macromolecules is higher for 3H-corticosterone. 3) In vivo and in vitro cell nuclear binding for both steroids showed the same pattern among the three tissues, but in vivo data showed more distinctly the preference of 3H-dexamethasone for the anterior pituitary and the preference of 3H-corticosterone for the hippocampus. 4) When labeled in tissue slices, cell nuclear radioactivity appears to be bound to macromolecules. 5) Steroid metabolism does not occur in slices during 60 min in vitro at 25 C and cannot account for the observed tissue differences in binding. The existence of more than one population of corticosteroid-binding sites in brain and in anterior pituitary is suggested. The results are consistent with the view that the dexamethasone blockade of stress-induced ACTH release is mediated by the anterior pituitary, while the high specificity of cotricosterone binding in the hippocampus implies a specific but as yet undetermined effect of the hormone in this brain area, an effect which may not be directly related to regulation of ACTH secretion.

Adrenalectomy↗
PubMed1992

Dexamethasone treatment increases mitochondrial RNA synthesis in a rat hepatoma cell line.

Glucocorticoid hormones act in the nucleus of the cell to alter expression of specific genes and change cell metabolism. In liver, these hormones have been reported to increase mitochondrial respiratory activity, which is regulated by both nuclear and mitochondrial gene products. We examined the effects of the synthetic glucocorticoid, dexamethasone, on the expression of mitochondrially encoded genes in a rat hepatoma cell line, H-4-II-E cells. Dexamethasone treatment of these cells increased mitochondrial RNA (mtRNA) levels 3- to 4-fold without changing the amount of mitochondrial DNA mtRNA levels could increase by enhanced mitochondrial gene transcription, by decreased degradation, or by some combination of the two. To determine if messenger RNA (mRNA) stabilization contributed to the increase in mtRNA levels, we compared the decay rates of cytochrome b mRNA from dexamethasone-treated and control cells after inhibition of RNA synthesis; cytochrome b mRNA half-life was 80 min in both treatment conditions. The levels of incompletely processed RNA precursors for at least two mtRNAs increased 3-fold more and 24 h earlier than the mature mRNAs. These results suggested that dexamethasone treatment resulted in increased mtRNA transcription. In addition, we examined the incorporation of [3H]uridine into mtRNA. Dexamethasone treatment expanded the uridine triphosphate pools 1.6-fold in H-4-II-E cells and decreased uridine triphosphate specific activity 2.3-fold; correcting for this change in precursor pool specific activity demonstrated increased mtRNA synthesis in dexamethasone-treated cells. Changes in expression of nuclear-encoded proteins that regulate mitochondrial genome transcription are a possible mechanism by which dexamethasone can increase mtRNA levels in these cells.

Adenosine Triphosphate↗
PubMed1992

Regulation of glucokinase and proinsulin gene expression and insulin secretion in RIN-m5F cells by dexamethasone, retinoic acid, and thyroid hormone.

In RIN-5mF cells, treatment with either dexamethasone or retinoic acid resulted in increased glucokinase activity. Treatment with dexamethasone (50 and 500 nM) increased glucokinase activity 140% and 260%, respectively, whereas treatment with retinoic acid (100 and 1000 nM) increased glucokinase activity by 50% and 80%, respectively. An additive effect was observed when 1000 nM retinoic acid was added to either 50 or 500 nM dexamethasone. Treatment with either of these factors resulted in increased glucokinase mRNA levels. In contrast, treatment with thyroid hormone (T3; 0.2 and 10 nM) had no effect on glucokinase activity, but decreased glucokinase mRNA levels. T3 did not affect the response of either activity or mRNA levels to retinoic acid. Binding experiments revealed the presence of a single class of T3 nuclear receptors, with a Kd of 0.46 x 10(-10) and a binding capacity of 3.84 pmol/mg protein in these cells. This suggests that the changes produced by T3 may be due to a physiological effect mediated via nuclear receptors. Proinsulin mRNA levels were increased by retinoic acid (10-100 nM) and dexamethasone (5-500 nM), but decreased by T3 (0.04-10 nM). Insulin secretion in the absence or presence of glucose and potassium was increased about 50% in cells previously treated with 1000 nM retinoic acid. T3 (0.2 nM) did not affect insulin secretion in the absence or presence of glucose or in the presence of secretagogues (potassium and glyceraldehyde). Dexamethasone (50 nM) did not significantly increase insulin secretion in the absence or presence of glucose or potassium. In contrast, dexamethasone decreased glyceraldehyde-induced insulin secretion by 60% (P less than 0.05). We conclude that the glucokinase and proinsulin genes respond in parallel to dexamethasone and retinoic acid (both increased) and to T3 (both decreased).

Animals↗
PubMed1993

Dexamethasone and calcium interact in the regulation of parathormone and chromogranin-A secretion and messenger ribonucleic acid levels in parathyroid cells.

We investigated the interaction of dexamethasone and Ca2+ on the secretion of PTH and chromogranin-A (CgA) by porcine parathyroid cells in culture and on the cellular levels of PTH and CgA mRNA. Freshly dispersed parathyroid cells were cultured for 6 days in Ham's F-12 medium containing 10% fetal calf serum and 1 mM Ca2+. The experiments were initiated at 0.5 or 3.0 mM Ca2+ in 0.5% serum with or without dexamethasone for an additional 24 or 48 h. Secretion of PTH and CgA was 50-60% less, and the respective mRNAs levels were about 75% lower at 3.0 than at 0.5 mM Ca2+. Dexamethasone (10(-9)-10(-7) M) stimulated the secretion of PTH in a dose-dependent fashion about 2-fold at both 3.0 and 0.5 mM Ca2+ and increased the PTH mRNA level 15-fold at the high and 3-fold at the low Ca2+ concentration. In contrast, the direction of action of dexamethasone on the secretion of CgA and CgA mRNA was dependent upon the Ca2+ concentration. At 3.0 mM Ca2+, dexamethasone increased CgA secretion and mRNA levels about 2- and 8-fold, respectively. In contrast, at 0.5 mM Ca2+ dexamethasone decreased CgA secretion to one half and its mRNA to one tenth that cells without the glucocorticoid. The stimulatory action of dexamethasone on PTH and CgA mRNA could be noted in 12 h or less and continued through 24-48 h. These results demonstrate a decoupling of PTH and CgA secretion and gene regulation. Our data accord with a role for CgA as an autocrine regulator of parathyroid gland secretion.

Animals↗
PubMed1995

Dexamethasone-induced antagonism of growth hormone (GH) action by down-regulation of GH binding in 3T3-F442A fibroblasts.

Supraphysiological levels of glucocorticoids, whether endogenous (Cushing's syndrome) or exogenous (glucocorticoid therapy), inhibit growth in children and immature animals. This effect has long been suspected to be due to glucocorticoid antagonism of GH action at the level of peripheral tissues. In the present study we demonstrate direct antagonism of GH action at the cellular level by the artificial glucocorticoid dexamethasone. Dexamethasone was found to inhibit the ability of GH to elicit several early events in GH signaling in 3T3-F442A fibroblasts. Dexamethasone (100 nM) for 24 h decreases by 50-75% GH-induced tyrosyl phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, the transcription factor Stat3/APRF, the GH receptor-associated tyrosine kinase JAK2, and the GH receptor. These effects appear to be specific to GH. Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or interleukin-6, or induction of JAK2 by leukemia inhibitory factor or interferon-gamma. Dexamethasone does not decrease the expression of ERK1 or -2, Stat3, or JAK2 proteins. Rather, the effects of dexamethasone on GH action appear to be due to a decrease in the number of GH receptors in the plasma membrane. Twenty-four-hour treatment with dexamethasone leads to a 50% decrease i GH binding, which Scatchard analysis suggests is due to a decrease in GH receptor number. These findings suggest that glucocorticoids antagonize cellular GH action by decreasing GH binding, suggesting a mechanism by which systemic glucocorticoids could antagonize GH action in peripheral tissues.

3T3 Cells↗
PubMed1978

Effects of dexamethasone on fetal and maternal thyroxine, triiodothyronine, reverse triiodothyronine, and thyrotropin levels.

The concentrations of T4, T3, rT3, and TSH were measured at term pregnancy in maternal and umbilical plasma and in amniotic fluid of 11 normal patients who received 8-16 mg dexamethasone 3-48 h before elective cesarean section and of 10 control patients who received no dexamethasone. The mean (+/- SE) concentrations of T4 (micrograms per dl) in maternal and umbilical plasma of dexamethasone-treated patients (12.5 +/- 0.9 and 13.0 +/- 0.9) were not significantly different (P less than 0.05) from those of the control patients (13.9 +/- 1.5 and 10.4 +/- 0.6, respectively). The mean (+/- SE) maternal plasma concentrations of T3 and rT3 (nanograms per dl) of dexamethasone-treated patients (204 +/- 6 and 82 +/- 11) were not significantly different (P less than 0.05) from those of the control patients (201 +/- 26 and 72 +/- 6, respectively). However, the mean (+/- SE) concentrations of T3 and rT3 (nanograms per dl) in umbilical plasma of dexamethasone-treated patients (106 +/- 13 and 360 +/- 35) were 3- and 2-fold and significantly higher (P less than 0.05) than those of the control group (39 +/- 6 and 195 +/- 19, respectively). No significant differences (P less than 0.05) were observed between the mean concentrations of TSH (microunits per ml) in maternal and umbilical plasma of dexamethasone-treated patients (2.5 +/- 0.5 and 3.0 +/- 1.0) and those of the control group (2.8 +/- 0.5 and 6.9 +/- 2.7, respectively). Under the conditions studied, no differences in the mean concentrations of amniotic fluid T4, T3, rT3, or TSH were observed between the two groups of patients (P less than 0.05). The increase of T3 and rT3 levels in umbilical plasma after dexamethasone administration indicates alteration in fetal thyroid economy.

Dexamethasone↗
PubMed1985

Sensitivity of cortisol and adrenal androgens to dexamethasone suppression in hirsute women.

To test the hypothesis that adrenal androgen secretion is more easily suppressed than is cortisol secretion by glucocorticoids, we examined the dose-response relationship for suppression of serum dehydroepiandrosterone (DHA), DHA sulfate (DHAS), testosterone, and cortisol by dexamethasone. Nine hirsute women received daily doses of dexamethasone, starting with 0.1 mg and increasing by 0.1-mg increments every 4 weeks, until the cortisol response to ACTH was reduced to 20% or less of the response before treatment. Serum hormone levels were measured at each dexamethasone dose before and after iv administration of 25 U synthetic ACTH. Although low doses of dexamethasone caused a similar suppression of basal cortisol, DHA, and DHAS levels, ACTH-stimulated DHA levels were suppressed to a greater extent than ACTH-stimulated cortisol levels. Higher dexamethasone doses did not result in a significant difference between the degree of cortisol and adrenal androgen suppression, as near-maximal suppression occurred for all three hormones. Maximal suppression of basal testosterone levels occurred at or below the dexamethasone dose of 0.3 mg. We conclude that the adrenal androgen secretory capacity is more sensitive to suppression by dexamethasone than is the adrenal cortisol secretory capacity. Furthermore, glucocorticoid therapy for hirsutism need not achieve complete cortisol suppression to effect a major reduction in adrenal androgen levels.

Adolescent↗
PubMed1991

Quantitative comparison of aromatase induction by dexamethasone in fibroblasts from a patient with familial cortisol resistance and a patient with cortisol hyperreactive syndrome.

The ability of dexamethasone to induce aromatase activity was tested in fibroblasts from a patient with familial cortisol resistance, a patient with cortisol hyperreactive syndrome, and five normal subjects. Dexamethasone increased enzyme activity in all cases in a concentration-dependent manner (over a range of 1-1000 nmol/L). In fibroblasts from a patient with familial cortisol resistance, the response curve of dexamethasone-induced aromatase activity was shifted to the right compared to that of normal cells. However, the maximal induction of the enzyme at 1 mumol/L dexamethasone was unchanged in cortisol-resistant fibroblasts. On the other hand, in fibroblasts from the patient with the cortisol hyperreactive syndrome, the half-maximal effect of dexamethasone was similar to that in normal cells, but maximum induction of aromatase activity was 2 times greater than that in normal cells. The glucocorticoid antagonist RU 486 inhibited dexamethasone-induced aromatase activity in these patients' cells and in normal cells in a concentration-dependent manner, indicating that the altered effects of dexamethasone on aromatase induction observed in each cell type were mediated through glucocorticoid receptors.

Aromatase↗
PubMed1992

Abnormal overnight dexamethasone suppression test in subjects receiving rifampicin therapy.

We have studied the effects of rifampicin on the overnight 1-mg dexamethasone suppression test usually employed to exclude suspected Cushing's syndrome. Previous observations indicate that in humans, rifampicin profoundly attenuates the biological effects of hydrocortisol and prednisolone, probably by increasing the metabolism of these drugs in the liver. The study was carried out in 16 normal volunteers. All subjects had a normal overnight 1-mg dexamethasone suppression test (468 +/- 86 vs. 32 +/- 21 nmol/L; mean +/- SD). In 8 subjects treated with rifampicin (600 mg) for 10 days, the inhibitory effect of dexamethasone on serum cortisol was completely prevented (575 +/- 114 vs. 434 +/- 82). In the remaining 8 rifampicin-treated subjects, the inhibitory effect of 1, 2, or 3 mg dexamethasone on serum cortisol was not observed. When 4 mg dexamethasone were administered, the serum cortisol level was 193 nmol/L, above the expected normal suppression value. The plasma dexamethasone concentration was very low after rifampicin treatment (range, 1.2-4.8 nmol/L). We conclude that when patients are treated with rifampicin, the standard overnight dexamethasone suppression test not only has no diagnostic value, but can be very misleading.

Adult↗
PubMed1997

Dexamethasone, OB gene, and leptin in humans; effect of exogenous hyperinsulinemia.

This study was undertaken to investigate temporal association between dexamethasone administration, OB gene expression, and leptin response in humans in the presence and absence of exogenous hyperinsulinemia. Six healthy males (age 24.5 +/- 1.0 yr, body mass index 26.4 +/- 1.0, body fat 16.2 +/- 1.8%) received 10 mg oral dexamethasone in five divided doses twice (protocols A and B) 1-2 weeks apart beginning at 0800 h on day 1 and ending at 0700 h on day 2. The dexamethasone administration was combined with two subcutaneous abdominal fat biopsies performed at 0800 h before and after dexamethasone administration (protocol A), or 4-h isoglycemic hyperinsulinemic (300 mU/m2 BSA/min, protocol B) clamp carried out between 0900 and 1300 h on day 2. OB gene expression (protocol A) did not change. In both protocols on day 2, the 0800 h leptin levels nearly doubled (P < 0.001), whereas 1300 h levels nearly quadrupled (P < 0.001). The elevation in leptin persisted until 0800 h of day 3 (24 h after last dexamethasone dose) with its subsequent rapid normalization. The short-term isoglycemic hyperinsulinemia (protocol B) had no additional effect on the postdexamethasone leptin response. We summarize that: 1) 24-h administration of dexamethasone has a marked stimulatory effect on circulating leptin levels but not on OB gene expression in the subcutaneous abdominal fat. 2) The effect is sustained for the next 24 h. 3) Short-term hyperinsulinemia has no additional effect. We conclude that dexamethasone is a powerful stimulator of leptin production in vivo through a mechanism that appears to be independent of OB gene transcription in the human subcutaneous abdominal fat.

Adipose Tissue↗
PubMed1999

Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor.

Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor alpha (TNFalpha, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNFalpha and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNFalpha or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbolmyristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNFalpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNFalpha and IL-10 secretion; whereas it suppressed TNFalpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNFalpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNFalpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNFalpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNFalpha or IL-10 pretreatment; TNFalpha blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy.

Adult↗