Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Involvement of the immunological mechanisms in atherogenesis has recently been suggested by immunohistological detection of macrophages and T lymphocytes in atherosclerotic lesions. In the present study, we have investigated the regulatory effect of interferon-gamma (IFN-gamma), a cytokine secreted by activated T cells, on the production and secretion of platelet-derived growth factor (PDGF) from macrophages in culture. The human monocytic leukemia cell line, THP-1, was treated with phorbol 12-myristate 13-acetate (PMA) for 24 h to induce macrophage differentiation and PDGF production, and then various doses of recombinant human IFN-gamma (0-1000 I.U./ml) were added to the culture. After 48 h, the conditioned medium and the cells were harvested and analyzed for PDGF production. PDGF-dependent mitogenic activity in the conditioned medium, estimated by neutralization of mitogenic activity with anti-PDGF antibody, was suppressed by IFN-gamma treatment. Radioimmunoassays for PDGF also revealed a decrease in both PDGF-AA and -BB in the conditioned medium with IFN-gamma treatment, whereas neither total cell DNA as an indication of cell number nor overall protein synthesis based on [3H]leucine incorporation were decreased. Northern analysis of total RNA extracted from the cells demonstrated that IFN-gamma suppressed the level of PDGF mRNA. Analysis of mRNA degradation in the presence of actinomycin D demonstrated that the decrease in PDGF mRNA was not due to enhanced degradation of mRNA. A similar inhibitory effect of IFN-gamma on PDGF mRNA levels was also found in monocyte-derived macrophages cultured in the presence of granulocyte-macrophage colony stimulating factor. These results suggest that IFN-gamma modulates production and secretion of PDGF from macrophages and that the functions of macrophages in atherogenesis may be regulated by the cellular interactions between T cells and macrophages through the action of cytokines such as IFN-gamma.
Atherosclerosis 1992 Nov
PMID:Interferon-gamma suppresses PDGF production from THP-1 cells and blood monocyte-derived macrophages. 144 96

The scavenger receptor (ScR) mediates uptake of chemically modified low density lipoprotein (LDL) by human monocyte-derived macrophages. It is not down-regulated by high intracellular cholesterol levels, and exposure of macrophages to acetylated or oxidized LDL therefore leads to foam cell development. The hypothesis that this represents an important mechanism for intracellular cholesterol accumulation in atherosclerosis is supported by the finding of ScR expression in foam cells of atherosclerotic plaques. T lymphocytes are also present in such plaques and it is known that T cell products regulate macrophage activation. We have therefore studied the effect of interferon-gamma (IFN gamma), a lymphokine secreted by activated T lymphocytes, on the expression of ScR in human monocyte-derived macrophages. Binding and uptake of acetylated LDL were significantly reduced in macrophages exposed to recombinant IFN gamma or IFN gamma-containing lymphocyte-conditioned media. Competition experiments showed that the IFN gamma-regulated binding and uptake of acetylated LDL was mediated via ScR. IFN gamma exerted its effect on the saturable binding of acetylated LDL by reducing the number of cell surface binding sites without significantly affecting the affinity between acetylated LDL and its receptor. Northern analysis revealed that the type I ScR mRNA was significantly reduced in IFN gamma-treated cells. Finally, IFN gamma treatment reduced intracellular cholesteryl ester accumulation and inhibited the development of foam cells in the cultures. In conclusion, our data show that IFN gamma blocks the development of macrophage-derived foam cells by inhibiting expression of ScR. This suggests that macrophage-T lymphocyte interactions may reduce intracellular cholesterol accumulation in the atherosclerotic plaque.
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PMID:Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. 155 91

Lipoprotein lipase (LPL) (EC 3.1.1.34) hydrolyzes triacylglycerols of very low density lipoproteins and chylomicrons. It is produced by several cell types, including macrophages, which are frequent in atherosclerotic lesions. The atherosclerotic plaque also contains activated T lymphocytes. We therefore investigated the possible regulatory effect of the T lymphocyte-derived lymphokine interferon-gamma (IFN-gamma) on macrophage LPL. Human monocyte-derived macrophages were treated with recombinant IFN-gamma or conditioned medium from activated peripheral blood mononuclear cells for 3 days. LPL activity was thereafter measured in the culture medium and in cell homogenates. The enzyme protein was detected at a cellular level by immunocytochemistry and immunopredicipitation. Recombinant IFN-gamma caused a profound decrease in macrophage LPL secretion. The IFN-gamma-treated cells, however, still contained immunodetectable enzyme and the decrease in secretion was apparently only partly due to an inhibited synthesis. Conditioned medium from activated peripheral blood mononuclear cells also drastically decreased the macrophage LPL secretion. When the conditioned medium was treated with antibodies against IFN-gamma, its down-regulating effect on macrophage LPL was totally removed. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis. A local release of IFN-gamma may be important in the pathogenesis of atherosclerosis by affecting the lipid accumulation in the lesion.
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PMID:Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. 211 81

During infection the vascular endothelial cell (EC) undergoes important immunologic alterations leading to increased leukocyte-EC adherence and initiation of a host inflammatory response. ECs express class 2 immune response genes and the interleukin 1 gene to a greater degree during infection and thus may be capable of amplifying the lymphocytic proliferative process. Lymphokines generated from stimulated lymphocytes, notably interferon-gamma, may in turn further enhance EC-leukocyte adherence and class 2 antigenic presentation by ECs. The ECs of different organ systems appear variable in terms of their immunologic capabilities. Infection of the endothelium has been demonstrated for an array of human pathogens, and even subclinical infection of ECs may ultimately assume importance in disease processes such as atherosclerosis. A potential role of the EC in the pathogenesis of newer infectious diseases, such as AIDS, is becoming evident and warrants further attention.
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PMID:Vascular endothelium in immunology and infectious disease. 249 65

Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin are inducible proteins involved in cell-cell adhesion. Immunohistochemical studies have indicated that human atherosclerotic plaques contain smooth muscle cells (SMCs) that express ICAM-1 and VCAM-1. Recently, we demonstrated that SMCs in culture express a functionally active cytokine-inducible ICAM-1. SMCs and mononuclear cells participate in the local accumulation of cytokines and related growth factors in atherosclerotic lesions. Therefore, we determined the effects of different cytokines and growth factors on mRNA content and cell surface expression of VCAM-1, ICAM-1, and E-selectin in cultured human aortic SMCs by Northern blotting, quantitative polymerase chain reaction amplification, and immunofluorescence flow cytometry. Under basal conditions of cultivation, both VCAM-1 mRNA and membrane expression of VCAM-1 were low and were induced very little by interleukin-1 beta (100 U/mL). Platelet-derived growth factor or transforming growth factor-beta decreased VCAM-1 mRNA basal expression. Treatment of SMCs with tumor necrosis factor-alpha (TNF-alpha) led to an increase in both VCAM-1 mRNA and cell surface expression for VCAM-1 in a dose- and time-dependent manner. Interferon-gamma induced a weak increase in VCAM-1 mRNA expression, with no synergistic effect on the stimulation by TNF-alpha. Various differences were noted between the expression of ICAM-1 and VCAM-1 genes, because interleukin-1 beta induced substantial amounts of ICAM-1 but not VCAM-1. The addition of interferon-gamma delays the time at which peak expression of ICAM-1 in response to TNF-alpha stimulation occurs. Under our conditions, we did not detect any expression of E-selectin by SMCs. These results suggest that cytokines regulate VCAM-1 and ICAM-1 expression on arterial SMCs and could play an important role in the pathophysiology of inflammatory and immune processes in atherosclerosis.
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PMID:Regulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular smooth muscle cells. 750 14

Vascular smooth muscle (VSM) cell proliferation contributes to the pathogenesis of atherosclerosis, restenosis after angioplasty and vein graft disease. The regulation of genes involved in VSM cell proliferation, particularly by naturally occurring inhibitors, is therefore of some importance. We have investigated the role of the c-myc proto-oncogene in growth arrest of exponentially proliferating rat VSM cells, following mitogen withdrawal, treatment with heparin (50 micrograms/ml), interferon-gamma (IFN-gamma) (100 i.u./ml), or the cyclic nucleotide analogues, 8-bromo-adenosine-3'5'-cyclic monophosphate (8-Br-cAMP; 0.1 mM) and 8-bromoguanosine-3'5'-cyclic monophosphate (8-Br-cGMP; 0.1 mM). Growth arrest was accompanied by down-regulation of c-Myc protein and mRNA following treatment with all inhibitors. Serum withdrawal or IFN-gamma treatment suppressed c-myc expression by more than 50% within 2 h, and this occurred throughout the cell cycle. Platelet-derived growth factor, epidermal growth factor and basic fibroblast growth factor all contributed independently to the maintenance of c-myc expression. Heparin, 8-Br-cAMP or 8-Br-cGMP also suppressed c-myc, but this occurred later, after 24-48 h, and was also observed following arrest by metabolic block. We conclude that c-myc expression is linked to VSM cell growth arrest in response to endogenous regulators and metabolic block. Down-regulation of c-myc expression may thus be an essential part of the arrest programme in VSM cells induced by many pharmacological agents.
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PMID:Down-regulation of the c-myc proto-oncogene in inhibition of vascular smooth-muscle cell proliferation: a signal for growth arrest? 752 76

P388D1 macrophage-like cells have previously been shown to produce both mitogenic and inhibitory regulators of porcine smooth muscle cell (pSMC) growth. The mitogenic activity was shown to have a molecular mass of > 10 kDa while the inhibitory activity was in the range of 2-6 kDa. In the present study, we present a novel dialysis culture system where P388D1 cells were grown in dialysis membranes with a 12 kDa cut-off which allowed continuous production of fractions of the culture medium. Using pSMC as target cells, mitogenic activity was found to be retained by the dialysis membrane while the low molecular mass inhibitory activity passed freely through the membrane. The effect of the macrophage-activators phorbol myristate acetate (PMA), concanavalin A (ConA) and interferon-gamma in combination with lipopolysaccharide (IFN gamma/LPS) were investigated in the dialysis culture system. PMA, ConA and IFN gamma/LPS were found to enhance the production of mitogenic activity by P388D1 cells. PMA also increased the production of growth-inhibitory activity, while ConA abolished inhibitor production and IFN gamma/LPS had no effect on the amount of inhibitory activity produced by P388D1 cells. The experiments show that the balance of production of mitogenic and inhibitory activities by macrophages can be modulated by agents that alter the state of activation of the cells. This could be of profound significance in the influence of macrophages on smooth muscle cell growth during the development of atherosclerosis.
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PMID:A dialysis culture system for the study of the production and modulation of growth-regulatory molecules: studies using the P388D1 macrophage cell line. 773 13

The fibrinolytic potential of the endothelial cells gives important antithrombotic properties to the vascular wall. Thrombosis is a frequent complication to atherosclerosis and other conditions where inflammatory mediators are present in the vascular wall. Inflammatory agents like lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF alpha) have been demonstrated to modulate the expression of fibrinolytic factors in cultured endothelial cells. In the present study the expression of tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) antigen in conditioned medium from cultured human umbilical vein (HUVEC) and human saphenous vein (HSVEC) endothelial cells was investigated under basal conditions and after stimulation with LPS, TNF alpha, interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) alone or in combinations. Stimulation with LPS or TNF alpha increased the expression of PAI-1, u-PA and PAI-2 in HUVEC and HSVEC, while the t-PA response differed between the two cell types. The effects of TNF alpha were modulated by IFN-gamma but not by IL-6. The increased expression of u-PA after stimulation with TNF alpha was reduced by IFN-gamma. In contrast, TNF alpha-induced expression of PAI-2 was synergistically increased by addition of IFN-gamma. These effects of IFN-gamma represent additional mechanisms by which inflammatory mediators may turn the fibrinolytic potential of the endothelium in a prothrombotic direction.
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PMID:Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. 777 58

The intercellular adhesion of circulating leukocytes to vascular endothelium is a prerequisite for leukocyte emigration from the blood to extravascular tissues. This process is facilitated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Both cultures contained similar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectively). Adhesion molecule expression was up-regulated by interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were more sensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expression were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke.
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PMID:Adhesion molecules on normotensive and hypertensive rat brain endothelial cells. 790 12

Atherosclerosis is characterized by cholesterol accumulation, inflammation, and fibrous tissue formation. We have analyzed inflammatory components of atherosclerotic plaques and obtained evidence for T lymphocyte activation and cytokine secretion. A molecular genetical characterization of T cell clones obtained from atherosclerotic lesions revealed that the cells are heterogeneous with regard to antigen receptor gene organization. This indicates that they are derived from several progenitors and respond to different antigenic epitopes. The latter are not yet known, and it is also unclear to what extent the lymphocytic infiltrate in plaques represent a local immune response. Vascular effects of cytokines produced by plaque macrophages and lymphocytes were studied in cell culture and animal experiments. It was found that the T cell cytokine, interferon-gamma, inhibits cholesterol accumulation and foam cell formation by down-regulating the scavenger receptor on macrophages. It also inhibits smooth muscle proliferation in culture and the formation of arterial restenosis after angioplasty in experimental animals. Together, these studies emphasize the importance of vascular-immune interactions in the pathogenesis of atherosclerosis.
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PMID:Immunological control mechanisms in plaque formation. 794 75


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