Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid, an anti-inflammatory agent, inhibits the development of atherosclerosis in various experimental animal models. This is partially explained by its ability to inhibit smooth muscle cell migration and proliferation in the intima and to reduce chemotaxis of circulating monocytes and leukocytes into the subendothelial spaces. We have recently demonstrated that oxidized LDL (Ox-LDL) has a mitogenic activity for macrophages in vitro in which Ox-LDL-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) production plays an important role. Proliferation of cellular components is one of the characteristic events in the development and progression of atherosclerotic lesions. In the present study, we investigated the effects of glucocorticoids on Ox-LDL-induced macrophage growth. Dexamethasone, prednisolone, and cortisol inhibited Ox-LDL-induced thymidine incorporation into macrophages by 85%, 70%, and 50%, respectively. Ox-LDL induced a significant production of GM-CSF by macrophages, which was effectively inhibited by dexamethasone, prednisolone, and cortisol by 80%, 65%, and 50%, respectively. Dexamethasone-mediated inhibition of Ox-LDL-induced GM-CSF mRNA expression and macrophage growth was significantly abrogated by RU-486, a glucocorticoid receptor antagonist. Our results suggest that the inhibitory effects of glucocorticoids on macrophage growth may be due to the inhibition of Ox-LDL-induced GM-CSF production through transactivation of the glucocorticoid receptor.
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PMID:Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor. 1039 91

Beclomethasone, budesonide, dexamethasone, and fluticasone propionate enhanced human eosinophil apoptosis in a concentration-dependent manner in vitro as assessed by flow cytometric analysis and morphological analysis. The order of potency was fluticasone propionate (EC(50) 3.7+/-1.8 nM) approximately budesonide (EC(50) 5.0+/-1.7 nM)>beclomethasone (EC(50) 51+/-19 nM)>dexamethasone (EC(50) 303+/-40 nM). Hydrocortisone, prednisolone, and prednisone (up to 1 microM) did not induce any significant increase in eosinophil apoptosis. The apoptosis promoting effects of glucocorticoids on eosinophils were reversed by an antagonist of glucocorticoid receptor mifepristone. The survival-prolonging effect of tumor necrosis factor (TNF)-alpha was reversed by dexamethasone and fluticasone (1 microM). In contrast, fluticasone, and dexamethasone (1 microM) did not reverse the survival-prolonging effects of interleukins-3 and -5 or granulocyte-macrophage colony-stimulating factor (GM-CSF). The results suggest that fluticasone and budesonide induce eosinophil apoptosis at clinically achievable drug concentrations via an effect on glucocorticoid receptor.
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PMID:Enhancement of human eosinophil apoptosis by fluticasone propionate, budesonide, and beclomethasone. 1104 Mar 38

Glucocorticoids acting through their specific receptor can either enhance or repress gene transcription. Dexamethasone represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor expression through a combination of direct inhibition of p65-associated histone acetyltransferase (HAT) activity and by recruiting histone deacetylase 2 (HDAC2) to the p65-HAT complex. Here we show that mifepristone, a glucocorticoid receptor partial agonist, has no ability to induce gene expression but represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor release by 50% maximally. Mifepristone was able to inhibit p65-associated HAT activity to the same extent as dexamethasone but failed to inhibit the natural promoter to an equal extent due to an inability to recruit HDAC2 to the p65-associated HAT complex. These data suggest that the maximal repressive actions of glucocorticoids require recruitment of HDAC2 to a p65-HAT complex. These data also suggest that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases.
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PMID:p65-activated histone acetyltransferase activity is repressed by glucocorticoids: mifepristone fails to recruit HDAC2 to the p65-HAT complex. 1139 7

Inhaled glucocorticoids are widely used to treat chronic obstructive pulmonary disease without much evidence of efficiency in this disease where neutrophils may contribute to the pathophysiology. This prompted us to test the effects of several currently used inhaled and systemic glucocorticoids on human neutrophil apoptosis. Beclomethasone, budesonide, dexamethasone, fluticasone propionate, hydrocortisone and prednisolone inhibited apoptosis in a concentration-dependent manner as assessed by flow cytometric analysis, annexin-V binding and morphological analysis. The maximal inhibition of apoptosis was 50-60%. The order of potency was fluticasone propionate (EC(50) 0.6+/-0.2 nM) approximately equal to budesonide (EC(50) 0.8+/-0.2 nM)> dexamethasone approximately equal to prednisolone approximately equal to beclomethasone approximately equal to hydrocortisone. The inhibitory effects of glucocorticoids were reversed by mifepristone. Moreover, glucocorticoids slightly enhanced the inhibitory effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on neutrophil apoptosis. The present data suggests that budesonide and fluticasone propionate prolong human neutrophil survival by inhibiting apoptosis at clinically relevant drug concentrations via an effect on glucocorticoid receptor.
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PMID:Beclomethasone, budesonide and fluticasone propionate inhibit human neutrophil apoptosis. 1173 Jul 31

The aim of this study was to investigate the role of the inhibitors of different PDE isoenzymes (PDE 1-5) on the production of two pro-inflammatory cytokines - tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Two in vitro models were used to compare the antiinflammatory properties of PDE inhibitors with that of glucocorticoids. The effect on TNF release from diluted human blood following lipopolysaccharide (LPS from Salmonella abortus equi) stimulation as well as the GM-CSF and TNF release from human nasal polyp cells following allergic stimulation were investigated. Both models proofed to be well suited for the characterisation of the antiinflammatory properties of new chemical entities. In diluted human blood and dispersed human nasal polyp cells the induced TNF release was most potently suppressed by selective PDE4 inhibitors. Amrinone and milrinone, selective PDE3 inhibitors, suppressed TNF secretion to a lesser extent. The effects of theophylline (unspecific PDE inhibitor), vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor) and the PDE5 inhibitors zaprinast and E 4021 were weak. In human blood, the tested glucocorticoids beclomethasone, dexamethasone and fluticasone inhibited the LPS induced TNF release potently in a concentration dependent manner, whereas in dispersed human nasal polyp cells, the effect of the glucocorticoids on allergically induced TNF release, with the exception of dexamethasone, was much less pronounced. Glucocorticoids were the most potent inhibitors of GM-CSF release and the effect correlates well with the affinity to the glucocorticoid receptor. The selective PDE 4 inhibitors, and to a certain extent the PDE3 inhibitors amrinone and milrinone, reduced the GM-CSF release in a concentration dependent manner. In all investigations selective PDE4 inhibitors reduced TNF release to a much higher degree (4-10 fold) than GM-CSF release.
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PMID:Modulation of TNF and GM-CSF release from dispersed human nasal polyp cells and human whole blood by inhibitors of different PDE isoenzymes and glucocorticoids. 1196 59

Mometasone is a potent synthetic glucocorticoid, which is under development as an inhaled preparation for the treatment of asthma. Previous studies have suggested that glucocorticoids have direct effects on human eosinophil and neutrophil apoptosis. The present study was designed to characterize the effects of mometasone on constitutive apoptosis and cytokine-afforded survival in isolated human eosinophils and neutrophils. The isolated eosinophils or neutrophils were cultured in vitro, and apoptosis was assessed by flow cytometric analysis of relative DNA content, by annexin-V binding and morphological analysis. Mometasone enhanced constitutive human eosinophil apoptosis in a concentration-dependent manner. The maximal enhancement of eosinophil apoptosis was 2.1-fold with an EC(50) value of 5.63 +/- 2.33 nM. This enhancing effect was reversed by the glucocorticoid receptor antagonist, mifepristone. In the presence of added cytokines, mometasone reversed tumor necrosis factor -alpha-induced eosinophil survival but not that afforded by interleukin -5. In contrast, mometasone inhibited human neutrophil apoptosis in a concentration-dependent manner. The maximal inhibition of neutrophil apoptosis was 50% with an EC(50) value of 0.17 +/- 0.03 nM. The inhibitory effect was partly reversed by mifepristone. In the presence of added cytokines, mometasone further enhanced neutrophil survival induced by the granulocyte-macrophage colony-stimulating factor and leukotriene B(4). The present data suggests that mometasone has opposite effects on apoptosis of human eosinophils and neutrophils at clinically relevant drug concentrations via an effect on glucocorticoid receptor.
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PMID:Divergent effect of mometasone on human eosinophil and neutrophil apoptosis. 1212 7

Glucocorticoids (GCS) inhibit mitogenesis of airway smooth muscle (ASM) cells grown on plastic. We have now evaluated the effects of GCS on proliferation of ASM grown on extracellular matrix proteins (ECM) abundant in noninflamed airways (laminin) and in fibrotic asthmatic airways (collagen type I). Dexamethasone inhibited basic fibroblast growth factor (bFGF)-induced proliferation in cells maintained on laminin, but not collagen. Cells grown on collagen were resistant to the anti-mitogenic actions of fluticasone propionate. In addition, dexamethasone did not inhibit thrombin-induced proliferation. Thus, resistance induced by collagen is not dependent on the mitogen and appears to be a class effect on GCS. The inhibition of bFGF-induced granulocyte-macrophage colony-stimulating factor production was unaffected by the ECM type on which cells were grown. The impaired anti-mitogenic activity of GCS in cells maintained on collagen may be due to a lack of efficacy against the collagen-amplified mitogenesis, rather than any defect in responsiveness that is specific to glucocorticoid receptor mechanisms.
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PMID:Collagen-induced resistance to glucocorticoid anti-mitogenic actions: a potential explanation of smooth muscle hyperplasia in the asthmatic remodelled airway. 1271 13

A new thyroid cancer cell line, KTC-2, was established from the malignant pleural effusion of a patient with recurrent thyroid cancer associated with anaplastic transformation from thyroid papillary cancer. Karyotype analysis showed a mode of 109 chromosomes. Subcutaneous cell injections produced small regressing tumors in athymic or severe combined immunodeficiency disorders (SCID) mice. Histologic examination showed anaplastic tumor cells surrounded by prominent mononuclear cells. An expression of thyroglobulin, thyroid transcription factor-1, and PAX-8 but not thyroid peroxidase and thyrotropin (TSH) receptor was detected. Biochemical analysis revealed secretion of interleukin (IL)-6, parathyroid hormone-related protein (PTHrP), and granulocyte-macrophage colony-stimulating factor. All the cytokines are known to induce paraneoplastic syndromes in patients with anaplastic thyroid cancer. Our previous studies revealed that medroxyprogesterone acetate (MPA) reduces secretion of IL-6 and PTHrP from human breast cancer cells. To investigate the regulatory mechanisms of secretion of these cytokines, MPA was administered to the KTC-2 cells. MPA dose-dependently decreased the secretion and mRNA expression of IL-6 and PTHrP. Expression of androgen receptor and glucocorticoid receptor (GR) but not progesterone receptor was detected. Dexamethasone but not dihydrotestosterone and progesterone decreased IL-6 and PTHrP secretion. These findings suggest that MPA decreases IL-6 and PTHrP secretion as a glucocorticoid mediated by GR in the KTC-2 cells. This KTC-2 cell line may be a suitable model for developing new strategies against paraneoplastic syndromes caused by anaplastic thyroid cancer.
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PMID:Medroxyprogesterone acetate decreases secretion of interleukin-6 and parathyroid hormone-related protein in a new anaplastic thyroid cancer cell line, KTC-2. 1272 73

The development of chronic sinusitis is a complex multifactorial process characterized by inflammation of nasal and sinus mucosa. Many studies have shown that the composition of the inflammatory substrate in chronic sinusitis is similar to that seen in allergic rhinitis and in the late-phase response to antigen challenge. Mononuclear cells, consisting of T and B lymphocytes and activated eosinophils, are prominent in the sinus mucosa of patients with chronic sinusitis, especially in atopic patients. Cellular recruitment and activation of the inflammatory infiltrate have been largely attributed to the effects of T(H)2 cytokines (namely interleukin -4, IL-5, IL-13, and granulocyte-macrophage colony-stimulating factor). Current treatment of allergic chronic sinusitis consists of nasal corticosteroids and immunotherapy. A subgroup of steroid-insensitive patients demonstrates an overexpression of a variant of the glucocorticoid receptor (GR). Despite these advances, the management and treatment of chronic sinusitis is often fraught with failures and remains a frustrating task for both physician and patient.
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PMID:Molecular immunology and immunotherapy for chronic sinusitis. 1453 72

1 We examined bone-marrow in mice receiving subcutaneous implants of heat-coagulated egg white, which are known to present chronic eosinophilic inflammation at the implant site. Egg white implants (EWIs) induced marked bone-marrow eosinophilia, and increased bone-marrow cell responses to granulocyte-macrophage colony-stimulating factor and interleukin-5 in culture. These effects were observed as early as 24 h and lasted for, at least, 30 days in implant recipients. 2 We found, however, that increased eosinophil production was also observed in control mice which underwent surgery but received no EWI (sham-implanted mice), up to 15 days post-surgery. As this suggests an important contribution of nonspecific stress mechanisms to eosinopoiesis, we further evaluated the role of stress hormones produced by the adrenal glands in the bone-marrow eosinophilia of sham-implanted mice. 3 Bone-marrow eosinophilia in mice undergoing surgery was dissociated from increases in other haemopoietic lineages. Surgery by itself increased circulating corticosterone levels by 24 h, and the increase was prevented by inhibition of adrenal glucocorticoid production by metyrapone. The effect of surgery on bone-marrow eosinophilia was prevented by pretreatment with both the glucocorticoid receptor antagonist, mifepristone, and metyrapone, and by surgical adrenalectomy. 4 By contrast, cathecolamine receptor antagonists (propranolol, prazosin and yohimbine) were ineffective, indicating that cathecolamine release from the adrenal glands was not responsible for the effects on bone-marrow. 5 These results highlight a critical role for stress-induced glucocorticoid hormones in selectively upregulating bone-marrow eosinopoiesis in mice submitted to surgery.
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PMID:Induction of bone-marrow eosinophilia in mice submitted to surgery is dependent on stress-induced secretion of glucocorticoids. 1538 31


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