Glucocorticoid Reduction Research Articles

Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunoglobulin

Background: Intravenous immunoglobulin (IVIG) has been used as an oral glucocorticoid (GC)–sparing agent in patients with steroid-dependent asthma. Despite its use, little is known regarding its mechanism of action. Objective: We sought to determine whether the GC-sparing effects of IVIG in severe asthma are related to improved GC receptor (GCR)–binding affinity and subsequent enhanced GC sensitivity. Methods: In an open-label study, 11 steroid-dependent asthmatic subjects (6 GC-insensitive, 5 GC-sensitive) received monthly infusions of IVIG (2 g/kg) for 6 months. Peak expiratory flow rates and oral GC dose were recorded daily, and spirometry was performed monthly. Blood was drawn for lymphocyte stimulation assays and GCR assays at baseline and after 3 and 6 months of therapy. Lymphocytes were stimulated ex vivo with PHA in the presence and absence of IVIG and increasing concentrations of dexamethasone (DEX). Results: IVIG resulted in significant reductions in oral GC dose ( P < .02), number of GC bursts ( P = .033), and hospitalizations ( P = .001) after 6 months of IVIG. Those with GC-insensitive asthma responded equally well to IVIG as those with GC-sensitive asthma. Associated with the improved clinical efficacy, IVIG acted synergistically with DEX in suppressing lymphocyte activation as measured by a shift in the DEX dose-response curve by 1 log-fold ( P = .03). IVIG therapy was also associated with significantly improved GCR-binding affinity ( P = .01). Conclusions: IVIG resulted in significant reductions in oral GC requirements and hospitalizations in a group of patients with severe asthma, with IVIG being as effective in patients with GC-insensitive asthma as in patients with GC-sensitive asthma. IVIG therapy acted synergistically with DEX in suppressing lymphocyte activation and significantly improved GCR-binding affinity after 3 and 6 months of therapy.(J Allergy Clin Immunol 1999;103:421-6.)

The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-γ production by cultured primary CD4 + T cells

This study was conducted to directly compare the in vitro efficacy and potency of several glucocorticoids in inhibiting T-cell cytokine production. The glucocorticoids tested were fluticasone propionate, budesonide, triamcinolone acetonide, and beclomethasone dipropionate, which are currently inhaled therapies for the treatment of allergic airway disease. Also used were betamethasone phosphate and the newly developed mometasone furorate. With a novel cell culture system, purified peripheral blood CD4 + T cells from normal donors were stimulated with immobilized anti-CD3 and soluble anti-CD28 monoclonal antibodies to induce high levels of IL-4, IL-5, and interferon-γ. By cell sorting, it was found that the IL-5 produced originated from memory cells, whereas both memory and naive cells produced interferon-γ. Mometasone and fluticasone inhibited IL-5 and IL-4 similarly (mometasone IL-5 inhibitory concentration of 50% = 0.27 ± 0.1 nmol/L and IL-4 = 0.19 ± 0.08 nmol/L). For both cytokines, the results indicate that mometasone and fluticasone were more potent than beclomethasone, triamcinolone, budesonide, and betamethasone. Of clinical importance is the finding that all steroids demonstrated less efficacy versus interferon-γ than IL-4 and IL-5. Glucocorticoid reduction of Th2 cytokines with lesser effects on interferon-γ would serve to reverse the exaggerated Th2 response that contributes to pathophysiology observed in allergic disease. Therefore the use of topically active glucocorticoids with low systemic bioactivity for the treatment of allergic inflammation may be particularly effective in modulating the cytokine activity that is an important component of the allergic response. (J Allergy Clin Immunol 1997;100:511-9.)

Developmental regulation of corticosteroid-binding globulin biosynthesis in the baboon fetus.

The present study determined the roles of estrogen and cortisol in maternal and fetal corticosteroid-binding globulin (CBG) levels and fetal hepatic messenger RNA (mRNA) expression in the baboon. Samples of fetal liver, kidney, and brain were obtained from untreated control animals at early (day 60; n = 4), mid (day 100; n = 8), and late (day 165; n = 5) gestation (term = day 184). Maternal and umbilical blood samples were collected on day 100 from baboons in which betamethasone was administered sc to the mother (n = 6) on days 60-99 of gestation and on day 165 from animals (n = 4) in which the fetus was administered betamethasone on days 150-164 of gestation. Maternal serum cortisol concentrations were similar at mid (43 +/- 2 micrograms/dl) and late (42 +/- 3 micrograms/dl) gestation and decreased (P < 0.05) at midgestation (1 +/- 1 micrograms/dl) and term (31 +/- 4 micrograms/dl) after betamethasone treatment. Umbilical serum cortisol levels were also reduced (P < 0.05) at both mid (1 +/- 1 micrograms/dl) and late (14 +/- 5 micrograms/dl) gestation by betamethasone treatment. Fetal serum CBG levels in untreated animals were lower (P < 0.05) on day 165 (444 +/- 29 pmol/ml) than on day 100 (844 +/- 35 pmol/ml) and increased (P < 0.05) at midgestation (1098 +/- 64 pmol/ml), but not at term (551 +/- 24 pmol/ml), after betamethasone treatment. In contrast, maternal serum CBG levels (range, 528-770 pmol/ml) were not altered by gestational age or betamethasone. The human CBG complementary DNA hybridized to a single mRNA species of 1.8 kilobases in baboon fetal liver; however, CBG was not expressed in fetal kidney and was detectable in fetal brain and pancreas only by reverse transcription-PCR. In untreated baboon fetuses, the mRNA levels of hepatic CBG, expressed as a ratio of 18S RNA, progressively decreased (P < 0.05) in early (1.83 +/- 0.17), mid (0.97 +/- 0.12), and late (0.51 +/- 0.04) gestation. These results demonstrate that fetal hepatic CBG mRNA expression and serum CBG concentrations were elevated early in baboon gestation and exhibited a progressive decline during the course of advancing pregnancy. We suggest that the increased levels of fetal CBG in the early stages of gestation reflect stimulation of hepatic CBG synthesis by maternal cortisol, which we previously demonstrated to occur in the fetus as a result of preferential 11 beta-hydroxysteroid dehydrogenase-catalyzed glucocorticoid reduction across the placenta. The decline in fetal CBG may reflect the developmental increase in catabolism of cortisol to bioinactive cortisone in target tissues of the fetus such as the liver.

Glucocorticoid reduction of bronchial epithelial inflammation during cardiopulmonary bypass.

Tumor necrosis factor-alpha (TNF-alpha) is released in inflammatory lung conditions, raising airway nitric oxide (NO) concentrations through the cytokine-mediated induction of nitric oxide synthase (NOS). Cardiopulmonary bypass (CPB) creates an inflammatory state, characterized by the release of TNF-alpha, that may result in lung injury following CPB. This study measured plasma levels of TNF-alpha and interleukin-6 (IL-6) as well as airway NO concentrations during CPB, and the effect of methylprednisolone (MPSS) on the levels of these inflammatory products. Twenty adult males scheduled for coronary artery bypass grafting (CABG) were anesthetized and randomized to a group given MPSS at 1 gm intravenously 5 min before CPB (Group S) or a group not given MPSS (Group N). Plasma levels of TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA) and the airway NO concentration by chemiluminescence. TNF-alpha was significantly (p < 0.05) increased at 30 min after the termination of CPB, while IL-6 was significantly (p < 0.05) increased at 50 min into CPB and 30 min after the end of CPB in Group N as compared with controls in the same group and with Group S at the same time intervals. A group of 10 patients undergoing repair of infrarenal aortic aneurysms, which served as a control group for plasma levels of TNF-alpha, showed no significant changes in TNF-alpha concentrations at any time during aneurysm repair. Airway NO increased significantly (p < 0.01) in Group N as compared with Group S at 5, 20, 35, and 50 min of CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid induction of Kv1.5 K+ channel gene expression in ventricle of rat heart.

Multiple voltage-gated K+ channels contribute to the repolarization phases of the cardiac action potential and are targets of several antiarrhythmic drugs. The Kv1.5 K+ channel gene is expressed in the heart, and heterologous expression of this gene generates a slowly inactivating K+ current. Previously, we found that glucocorticoids specifically upregulate pituitary Kv1.5 gene expression. To test whether these steroids might also induce Kv1.5 gene expression in the heart, cardiac channel mRNA and protein were measured by RNase protection assay and by immunoblotting with antibody specific for the extracellular domain of Kv1.5 polypeptide. Kv1.5 mRNA and immunoreactive protein appeared to be more abundant in rat ventricle than atrium. Reduction of endogenous glucocorticoids by adrenalectomy decreased ventricular Kv1.5 mRNA approximately 8-fold, which was estimated by using cyclophilin mRNA as an internal control. Kv1.5 immunoreactive protein also decreased approximately 6-fold. Injection of dexamethasone into adrenalectomized rats acted within a day to increase ventricular Kv1.5 mRNA and immunoreactive protein approximately 50-fold and approximately 20-fold, respectively. In contrast, atrial Kv1.5 mRNA expression was unaffected by either adrenalectomy or injection of the glucocorticoid agonist. Furthermore, dexamethasone-induced upregulation was specific for Kv1.5, since whole-heart Kv1.4 and Kv2.1 mRNA levels, as well as ventricular Kv2.1 mRNA expression, were unchanged. Thus, dexamethasone specifically upregulates Kv1.5 K+ channel gene expression in rat ventricle but not atrium. Glucocorticoids may affect excitability of ventricular myocytes and the efficacy of clinically useful drugs by changing the expression of the Kv1.5 K+ channel.

Anspruch und Wirklichkeit der antirheumatisch medikamentösen Therapie

The antiinflammatory therapy by patients with rheumatoid arthritis at the time of their first surgery was analysed in a retrospective study. 100 non-selected patients with rheumatoid arthritis and indication for surgery were investigated. All patients have been reexaminded or have been interviewed on their disease by phone. The result of this study shows that the onset of an adequate antirheumatoid medication, which includes basic therapy and alleviating agents, was undoubtly delayed. The antirheumatoid medication of these patients at the time of their first surgery was, in most cases not in accordance with commonly accepted rheumatoid regimes. The use of glucocorticoids was too high. To improve the antirheumatoid medication in patients with rheumatoid arthritis, a therapy between the general practitioner on the one hand and rheumatoidorientated physicians and orthopaedic specialists on the other should be performed routinely. The application of antirheumatoid medication, including basic and alleviating agents, should be performed in time, under constant control. In case this proves ineffective, or if there are side effects, medication must be changed. Continuity of adequate antirheumatoid medication must be ensured after surgery. Reduction of glucocorticoids is a mandatory aim of therapy.

Adrenal Glucocorticoids Regulate Adipsin Gene Expression in Genetically Obese Mice

Adipsin expression at the protein and mRNA levels is greatly reduced in several distinct syndromes of obesity in the mouse: genetic obesity due to the db/db and ob/ob genes, and a chemically induced model secondary to neonatal exposure to monosodium glutamate. We considered first the possibility that the adipsin gene might be identical to the db or ob locus and the lowered expression of this protein might result from a mutation in this gene. We show here that the adipsin structural gene is located on chromosome 10 and hence is physically distinct from any obesity genes so far identified in the mouse. A major role for the adrenal gland and adrenal glucocorticoids in the aberrant regulation of adipsin in these models of obesity is indicated by several experiments. Adrenalectomy of the ob/ob mouse raises the circulating levels of adipsin protein and the amount of this mRNA in epididymal fat pads (5-fold), although neither is increased to the levels seen in lean controls. Exogenous administration of corticosterone completely blocks the effects of adrenalectomy on adipsin, suggesting that the effect of this endocrine ablation is through reduction of adrenal glucocorticoids. Corticosterone administration also causes suppression in the levels of adipsin mRNA and protein in lean mice, although this decrease is never as severe as that seen in obese mice. The effect of exogenous corticosterone in lean mice occurs within 2 days and hence is not secondary to the obesity which these hormones eventually elicit. These results indicate that glucocorticoids can regulate adipsin expression in vivo and strongly suggest that the hyperglucocorticoid state seen in certain obese models plays a significant role in lowering adipsin mRNA and protein levels. Quantitative analysis of these experiments suggests that other as yet unknown neuroendocrine factors also function to suppress adipsin in obesity.