UNIPROT:P04141 - FACTA Search

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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)

Oxidized lipoproteins have been identified in atherosclerotic plaques and in early lesions in humans as well as in animals. There is accumulating evidence that such oxidized lipoproteins have an important role in atherosclerosis. Treatment of endothelial cells with altered lipoproteins stimulates monocyte binding as well as the production of chemotactic factors for monocytes. Both these findings could be relevant to the accumulation of monocytes-macrophages in the arterial wall during the early stages of lesion development. We now report that treatment of endothelial cells (EC) with modified low-density lipoproteins obtained by mild iron oxidation or by prolonged storage, results in a rapid and large induction of the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF (M-CSF) and granulocyte CSF (G-CSF). These growth factors affect the differentiation, survival, proliferation, migration and metabolism of macrophages/granulocytes, and G-CSF and GM-CSF also affect the migration and proliferation of EC. Because EC and macrophages are important in the development of atherosclerosis, the expression of the CSFs by these cells could contribute to the disease.
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PMID:Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. 169 Mar 54

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein hormone that stimulates the growth of hematopoietic progenitor cells and enhances the functional activity of mature myeloid effector cells. Granulocyte-macrophage colony-stimulating factor was administered to eight patients with severe aplastic anemia in an attempt to restore adequate hematopoiesis. Profound decreases in serum cholesterol concentrations were observed during GM-CSF therapy that were not dependent on changes in the patients' peripheral blood cell counts. Serum cholesterol levels decreased by an average of 37% during treatment, reaching levels of less than 4.40 mmol/L in all patients. Serum cholesterol concentrations returned to baseline in all patients after discontinuation of GM-CSF therapy. Treatment with GM-CSF prominently alters cholesterol homeostasis in vivo, although the mechanism of this effect is unknown. Our results suggest that GM-CSF may be potentially useful in the treatment of hypercholesterolemia and, possibly, in the prevention and treatment of atherosclerosis.
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PMID:Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor. 264 96

Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion molecules, enhances cytokine production, and induces tissue factor procoagulant activity. In the present study, we have examined the relative roles of the two cell surface receptors for TNF-alpha (p55 and p75) on endothelial cells, using antibodies with both agonistic and antagonistic activities. We report that anti-p55 receptor agonistic antibody Htr-9 induces the expression of tissue factor antigen and the release of interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In contrast, there is very little or no activation of endothelial cell responses by an anti-p75 agonist. TNF-alpha-induced expression of tissue factor and adhesion molecules, and release of IL-8 and GM-CSF, are decreased by antibodies with antagonistic activities for either receptor, although the effect of anti-p55 antibodies is markedly greater than that of anti-p75 antibodies. The responses of endothelial cells to lymphotoxin/TNF-beta are significantly decreased by anti-p55 antagonists alone. Our data suggest that endothelial cell responses to TNF-alpha, such as expression of tissue factor and adhesion molecules for mononuclear cells, which may be important in the pathogenesis of atherosclerosis, are mediated predominantly, but not exclusively, by the p55 TNF receptor.
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PMID:Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells. 791 75

Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of a family of cytokines that regulate proliferation in macrophages and other types of cells, has been implicated in the inflammatory-fibroproliferative response of atherosclerosis. However, previous studies have been restricted to cultured cells and animal models. In the present study, we investigated GM-CSF expression in undiseased and atherosclerotic human coronary arteries at both the mRNA and protein levels. Dual in situ hybridization/cell-marking experiments demonstrated that subpopulations of intimal smooth muscle cells (SMCs) and endothelial cells express the cytokine in the histologically normal human coronary artery and that augmented expression occurs at these sites, and in macrophage accumulations and medial SMCs, in the atherosclerotic vessel. Corresponding data were obtained by in situ hybridization and reverse transcription-polymerase chain reaction and Northern analyses of cultured cells. Cultured human coronary arterial SMCs showed constitutive expression of GM-CSF in cells that had adopted an activated synthetic phenotype. Electron microscope immunocytochemistry revealed that GM-CSF is a protein localized in the cytoplasmic matrix of SMCs of both the undiseased and atherosclerotic vessel wall; extracellular matrix was largely unlabeled, with only occasional small patches of amorphous immunopositive material. The expression of GM-CSF by subpopulations of intimal SMCs in the undiseased artery and the marked upregulation of GM-CSF apparent in atherosclerotic lesions suggest roles for the cytokine in the cellular events underlying initiation and progression of the human atherosclerotic lesion.
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PMID:Smooth muscle cells express granulocyte-macrophage colony-stimulating factor in the undiseased and atherosclerotic human coronary artery. 940 19

Atherogenesis is a multifactorial chronic inflammatory disease in which low plasma levels of HDLs are a strong predictor of the condition. Although the mechanism of protection by HDLs is not precisely known, HDLs have been shown to influence many of the events involved in the development of atherosclerosis. Previously we have shown that HDLs inhibited the cytokine-induced expression of adhesion molecules (E-selectin, VCAM-1, and ICAM-1) by endothelial cells (ECs). As the complete transcriptional regulation of all 3 genes requires the NF-kappaB family of transcription factors, we examined the effect of HDLs on activation of NF-kappaB. We also investigated the effect of HDLs on 2 other cytokine-induced genes, granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclooxygenase (Cox-2; prostaglandin H2 synthase, EC 0.1.14.99.1). E-selectin expression in response to tumor necrosis factor-alpha (TNFalpha) was, as expected, inhibited in ECs that had been preincubated with HDLs. However, the level of secretion of GM-CSF in the same cultures was no different from control. In a similar manner, although HDLs had no effect on steady-state mRNA levels of GM-CSF, the levels of E-selectin were significantly inhibited by HDLs. In transient cotransfection experiments we found that HDLs inhibited the cytokine-induced expression of a reporter gene driven by the E-selectin proximal promoter (-383 to 80) but had no effect on the expression of a reporter gene driven under the control of the proximal promoter of GM-CSF (-627 to 28). As would be predicted from this differential response, HDLs did not influence the nuclear translocation or DNA binding of NF-kappaB, or alter the kinetics of degradation and resynthesis of the inhibitory protein IkappaBalpha. We found that HDLs synergized with cytokine to enhance the expression of Cox-2 and induce the synthesis of its main EC product, prostacyclin (PGI2), a potent inhibitor of platelet and leukocyte functions. In conclusion, HDL induces an antiinflammatory phenotype in cytokine-induced ECs, synergizing with cytokine to induce elevation of Cox-2 in addition to inhibiting adhesion molecule expression. Our studies show that these differential effects are mediated in a manner that is likely to be independent of NF-kappaB per se.
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PMID:High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2. 1019 17

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

Chemoattraction of monocytes by the CXC chemokine stromal cell-derived factor-1alpha (SDF-1alpha) and its receptor CXCR4 may be involved in vascular diseases like atherosclerosis. We studied the regulation of CXCR4 transcription and SDF-1-induced functional responses in human monocytes during their differentiation in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), oxidized low-density lipoprotein (Ox-LDL), and unmodified LDL. Our results reveal that the rapid decline of SDF-1-mediated [Ca2+]i influx after monocyte isolation is followed by a gradual functional restoration and a concomitant reexpression of CXCR4 mRNA over time. A further three- to fourfold induction of CXCR4 mRNA occurred in macrophage-derived foam cells on treatment with Ox-LDL. HL-60 cells induced with phorbol myristate acetate (PMA) showed a rapid fourfold stimulation of CXCR4 mRNA within 1 h, declining to barely detectable levels at 3 h, with eventual restoration over time, mirroring the expression pattern in monocytes. Surface expression of CXCR4 is maintained in HL-60 cells during PMA-induced differentiation, as demonstrated by flow cytometry. GM-CSF had no effect on CXCR4 mRNA in HL-60 cells and does not cause its down-regulation in human macrophages.
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PMID:Modulation of CXCR4 expression and SDF-1alpha functional activity during differentiation of human monocytes and macrophages. 1041 Oct 1

Oxidized LDL can induce an increase in intracellular calcium concentration and the activation of protein kinase C in mouse peritoneal macrophages. The activation of protein kinase C leads to the release into the culture medium of granulocyte-macrophage colony-stimulating factor, which plays a priming role in oxidized LDL-induced macrophage proliferation. The expression of granulocyte-macrophage colony-stimulating factor in macrophages by oxidized LDL is positively regulated in the 5'-flanking region of granulocyte-macrophage colony-stimulating factor gene from sequence -169 to -160, but negatively regulated from -91 to -82. Granulocyte-macrophage colony-stimulating factor released by oxidized LDL from macrophages induces proliferation in autocrine or paracrine fashion via the activation of phosphatidylinositol 3-kinase. The capacity of oxidized LDL to induce macrophage proliferation in vitro may be involved in the enhanced progression of atherosclerosis in vivo.
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PMID:Macrophage proliferation in atherosclerosis. 1104 93

Cytokine activation of vascular endothelial cells renders the hyperadhesiveness for neutrophils. During the processes of inflammation and atherosclerosis, the production of reactive oxygen species by neutrophils contributes to endothelial cell (EC) damage and injury. However, the precise mechanisms for neutrophil activation by ECs remain unknown. Thus, we investigated what kinds of pathophysiological factors synthesized by inflammatory cytokine-activated ECs potentiated the activity of neutrophil functions. The magnitude of O(2)(-) release from neutrophils, which is one of pivotal neutrophil functions, was measured as an indicator potentiated by activated ECs. Neutrophils release massive amounts of O(2)(-) on coculture with activated ECs. Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody (Ab) or specific platelet-activating factor (PAF)-receptor antagonist suppressed the O(2)(-) release from neutrophils on coculture with the activated ECs by 50% to 70%. The supernatants from activated ECs also induced O(2)(-) release by neutrophils. This stimulatory effect of activated EC supernatants on O(2)(-) release by neutrophils was abolished by anti-GM-CSF Ab or by PAF-receptor antagonist. As we previously reported, we demonstrated the expression of GM-CSF mRNA by Northern blotting and protein synthesis of GM-CSF by ELISA on tumor necrosis factor as well as interleukin-1-activated ECs. Although phosphorylation of mitogen-activated protein kinases was observed in ECs stimulated by tumor necrosis factor and interleukin-1, treatment of ECs with PD98059 (MEK1 inhibitor) and SB203580 (p38 mitogen-activated protein kinase inhibitor) in the presence of the cytokine failed to attenuate the stimulatory effect of activated ECs on neutrophil activation. We found that activated ECs regulated neutrophil function on coculture. We show here for the first time, to our knowledge, that the collaboration between GM-CSF and PAF synthesized by activated ECs markedly potentiated neutrophil activation.
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PMID:Activation of human neutrophil by cytokine-activated endothelial cells. 1123 Jan 10

Atherosclerosis is increasingly recognized as an inflammatory disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine, recently implicated as a prominent component of the regulatory network involved in atherogenesis. We aimed to study the relationship between circulating GM-CSF levels and serum fatty acid (FA) composition in 78 healthy subjects. The latter was analyzed by gas-liquid chromatography and GM-CSF by a high-sensitivity commercial enzyme-linked immunosorbent assay (ELISA). Among women (n = 40), serum GM-CSF levels were found to be positively associated with the proportion of palmitic acid (C16:0) and negatively with linoleic acid (C18:2omega-6), docosahexaenoic acid (DHA, C22:6omega-3), and the proportion of total essential FA. After excluding smoking women (n = 6), the associations among GM-CSF and serum linoleic acid concentration (r = -0.49, P =.003), arachidonic acid (r = -0.52, P =.001), and DHA (r = -0.34, P =.04) were strengthened. The ratio of palmitic to linoleic and DHA acids was the single best predictor of serum GM-CSF in all subjects. Together with arachidonic acid, it contributed to 22% of the GM-CSF variance in women, after taking into account the effects of age, body mass index (BMI), blood pressure, and smoking status. None of these associations were observed among men. In conclusion, serum FA composition is associated with circulating GM-CSF specifically in women. As human arterial and venous smooth muscle cells release GM-CSF, and treatment of endothelial cells with oxidized low-density lipoproteins results in a rapid expression of GM-CSF, the mechanisms involved in these associations and the sex-linked differences should be further explored.
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PMID:Circulating granulocyte-macrophage colony-stimulating factor and serum fatty acid composition in men and women. 1173 97

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