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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of transforming growth factor-beta 1 (TGF-beta 1) and interleukin-1 beta (IL-1 beta) on LDL receptor in Hep G2 cells was investigated. A greater than two-fold stimulation of the binding and internalisation of [125I]-labelled LDL at 37 degrees C was observed after an 18-h incubation of the cells with TGF-beta 1 at 50 ng/ml and IL-1 beta at 11,700 units/ml compared with control cells. Scatchard analysis of the binding of [125I]-labelled LDL at 4 degrees C after an 18-h incubation of the cells with 1170 units/ml IL-1 beta and 5 ng/ml TGF-beta 1 showed that they were both acting primarily by increasing LDL receptor number. The increase in LDL receptor activity could not be attributed to an increase in cell proliferation as TGF-beta 1 at concentrations from 0.05 ng/ml to 50 ng/ml had no significant effect on either cell number or [3H]thymidine incorporation into DNA whilst IL-1 beta inhibited DNA synthesis by more than 80% at a concentration of 11,700 units/ml but had significant effect on cell number. Cholesterol biosynthesis from [14C]acetate, in contrast to the stimulation of LDL receptor activity, was inhibited by approximately two-fold by incubation with TGF-beta 1 at 50 ng/ml and IL-1 beta at 11,700 units/ml.
Atherosclerosis 1992 Nov
PMID:Transforming growth factor-beta 1 and interleukin-1 beta stimulate LDL receptor activity in Hep G2 cells. 144 91

Biosynthesis of apolipoprotein (apo) E has been previously demonstrated to be regulated in macrophages by intracellular free cholesterol levels as well as by macrophage activating factors. In this report, the regulation of apo E secretion by cytokines detected within atherosclerotic lesions has been investigated. Granulocyte macrophage-colony stimulating factor (GM-CSF) stimulated macrophages had a 3-5-fold reduction in apo E secretion, comparable to that observed for gamma interferon (IFN gamma), while tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) resulted in a 2-fold decrease. In contrast to the reduction in apo E secretion by these cytokines, transforming growth factor beta (TGF-beta) stimulated macrophages secreted 3-fold greater amounts of apo E than controls. The reduced secretion of apo E by GM-CSF was reversible, heat labile, dose dependent, maximal 48 h after cytokine exposure and was coincident with an increase in fibronectin secretion. The opposing effects of GM-CSF and TGF-beta on apo E secretion were consistent with similar changes detected in apo E mRNA levels. Cytokine effects on apo E secretion in cholesterol loaded macrophages were also investigated and found to be similar to the non-loaded cells with GM-CSF decreasing and TGF-beta increasing apo E secretion. The observed differences in apo E secretion did not correlate with any significant changes in either cellular cholesterol distribution in the non-cholesterol loaded macrophages or in basal ACAT activity. In addition to changes in apo E secretion, cytokine treated macrophages pulsed with [14C]oleate and acetylated LDL for 2-6 h had a 2-fold increase (GM-CSF) or decrease (TGF-beta) in cholesterol esterification. Therefore, GM-CSF and TGF-beta mediated changes in apo E secretion may occur through a mechanism independent of changes in cellular free cholesterol levels. These results suggest that cytokines expressed within an atheroma may play an important role in the modulation of macrophage mediated reverse cholesterol transport.
Atherosclerosis 1992 Oct
PMID:Cytokine regulation of macrophage apo E secretion: opposing effects of GM-CSF and TGF-beta. 146 52

Foam cell formation via lipid accumulation through the scavenger receptor in human monocyte/macrophages is believed to be one of the earliest events in atherogenesis. In this study we demonstrate that stimulation of the scavenger receptor activates monocytes to produce interleukin-1 (IL-1). Polyinosinic acid (poly I) and fucoidan, both ligands known to bind to the scavenger receptor, induced IL-1 beta production in human monocytes. Polycytidylic acid, a structurally related compound to poly I, which does not bind to the scavenger receptor, was used as a negative control and had virtually no effect on IL-1 production. THP-1 cells, which normally do not express scavenger receptors, were almost unresponsive to poly I and fucoidan. PMA priming, which has been reported to up-regulate scavenger receptor expression in THP-1 cells, significantly enhanced IL-1 production by fucoidan and poly I. IL-1 produced by scavenger receptor stimulation was shown to be secreted extracellularly, and biologically active. Scavenger receptor-mediated IL-1 production was inhibited by H7, a protein kinase C inhibitor, and enhanced by IBMX, an inhibitor of cyclic AMP degradation, suggesting a synergistic effect of protein kinase C and cyclic AMP-mediated signal transduction pathways in scavenger receptor-mediated IL-1 production. Due to the potentially deleterious effects of IL-1 on the vessel wall, IL-1 produced by ligand binding to the scavenger receptor in human monocytes may play a role in the pathogenesis of atherosclerosis.
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PMID:Induction of interleukin-1 production by ligands binding to the scavenger receptor in human monocytes and the THP-1 cell line. 166 75

The cytokine interleukin-1, IL-1, likely plays an important role in the early stages of atherogenesis. The possible action of probucol and tocopherol on the expression and secretion of IL-1 beta was investigated using the human monocytic leukemia cell line, THP-1. Both probucol and D-alpha-tocopherol inhibit the phorbol ester-induced release of IL-1 beta without altering differentiation. Analysis of IL-1 beta mRNA levels revealed that probucol and tocopherol had an inhibitory effect on the activation of expression of the IL-1 beta gene. The data suggest that the beneficial effects of probucol may be related to inhibition of IL-1 at an early phase of atherosclerotic plaque formation.
Atherosclerosis 1991 Feb
PMID:Inhibition of IL-1 beta expression in THP-1 cells by probucol and tocopherol. 187 19

Interleukin-1 (IL-1) has been implicated as a regulatory protein in the development and clinical sequelae of atherosclerosis. To determine which cells in the atherosclerotic plaque synthesize IL-1 in situ, the authors evaluated histologic sections of iliac arteries from cynomolgus monkeys using probes for IL-1 alpha and beta. A polyclonal antibody to IL-1 alpha and beta was used to determine if proteins were concomitantly produced. The predominant cells expressing IL-1 alpha and beta mRNA were foam cells in the intima. Adherent leukocytes and vascular smooth muscle cells (VSMCs) expressed mRNA for IL-1 alpha. Microvascular endothelium expressed mRNA for both IL-1 alpha and beta. IL-1 proteins were located frequently in cells expressing IL-1 mRNA. These results indicate that endothelium and VSMCs, in conjunction with macrophages, serve as localized sources of IL-1 protein synthesis. These findings suggest that vascular cells may contribute directly to the pathogenesis of atherosclerotic vascular disease by actively secreting potent biologic mediators that modify vascular and immune cell function.
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PMID:Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis. 201 78

The authors have investigated the effects of cytokines and lipopolysaccharide (LPS) on mRNA levels of c-sis (platelet-derived growth factor (PDGF)-B chain), PDGF-A chain, and interleukin 1 beta (IL-1 beta) genes in human vascular endothelial cells (EC). IL-1, tumor necrosis factor (TNF), and LPS not only enhanced the accumulation of c-sis mRNA, but also induced IL-1 beta gene expression. Interferon-gamma (IFN-gamma), in contrast, suppressed the accumulation of c-sis mRNA profoundly and PDGF-A chain mRNA to a lesser extent. The cytokine, in addition, suppressed the release of PDGF-like proteins by EC, while maintaining the growth of EC. IFN-gamma, however, augmented the levels of IL-1 beta mRNA in cultured EC in association with LPS or IL-1, suggesting that the suppression of c-sis expression was not mediated through modulation of IL-1 gene expression by IFN-gamma. These results raise the possibility that IFN-gamma may play a novel regulatory role in the pathogenesis of vascular diseases such as atherosclerosis and vasculitis.
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PMID:Interferon-gamma modulates messenger RNA levels of c-sis (PDGF-B chain), PDGF-A chain, and IL-1 beta genes in human vascular endothelial cells. 249 3

We report that interleukin-1 (IL-1) potentiates the proliferation of vascular smooth muscle cells. Growth of early passage smooth muscle cells was not significantly affected by IL-1 alone. Treatment with IL-1 together with the platelet derived growth factor (PDGF) or another polypeptide growth factor derived from mitogen activated human monocytes (MDGF) resulted in a significant enhancement of cell growth over either PDGF or MDGF alone. DNA synthesis was enhanced only marginally (30-40%) in quiescent cultures treated with an optimal concentration of IL-1 alone. In the presence of 5 units/ml of PDGF or MDGF, IL-1 produced about six- to eightfold higher DNA synthesis than the untreated cultures. Induction of DNA synthesis was linear between 0.1 and 1.0 pM IL-1, dependent on PDGF concentration, and was effectively neutralized by monoclonal antibodies against IL-1 beta. The growth promoting activity of IL-1 was extremely potent producing half-maximum stimulation at a concentration of 0.5 pM. These results suggest that IL-1 may play an important role in the modulation of growth and other activities of vascular smooth muscle cells. These observations are especially important with regard to defining the potential macrophage derived mediators contributing to vascular cell proliferation during inflammation and the pathogenesis of atherosclerosis. It is shown here that elicitation of IL-1 induced growth response requires a coordinated action with another priming growth factor such as PDGF. In this regard, IL-1 mediated proliferation of smooth muscle cells may have analogy with the IL-1 mediated T-cell activation and IL-2 production where concerted actions of antigen/mitogen and IL-1 are required.
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PMID:Interleukin-1 promotes proliferation of vascular smooth muscle cells in coordination with PDGF or a monocyte derived growth factor. 278 86

Intravenous injection of 1.5 mg of acetylated low-density lipoprotein (LDL) or 100 micrograms of lipopolysaccharide (LPS) to zymosan-primed mice induced a decrease in serum zinc levels measured 6 hours after injection, suggesting the release of interleukin 1 (IL-1). Oral administration of probucol, 100 mg/kg once daily for 14 days, inhibited the LPS-induced fall in serum zinc levels, suggesting inhibition of IL-1 release. Direct evidence for inhibition of IL-1 release by probucol was obtained with an ex vivo system in which, compared with controls, peritoneal macrophages from probucol-treated mice (100 mg/kg orally X 3, or 0.25% in the diet for 3 weeks) secreted 80 to 90% less IL-1 upon LPS stimulation, measured by the C3H/HeJ thymocyte proliferation assay. Inhibition of IL-1 secretion by probucol may contribute to the therapeutic effect of probucol in atherosclerosis since as little as 1 unit of recombinant IL-1 beta was found to induce proliferation of aortic smooth muscle cells. With regard to the endogenous stimulus for IL-1 secretion, oxidized LDL is a putative candidate because it is capable of stimulating peritoneal macrophages to secrete IL-1. Because oxidized LDL is involved in the transformation of macrophages to foam cells, our data on IL-1 induction by oxidized LDL and the mitogenic effect of IL-1 on aortic smooth muscle cells suggest that activated macrophages play an important role in atherogenesis.
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PMID:Inhibition by probucol of interleukin 1 secretion and its implication in atherosclerosis. 326 Jul 41

Interleukin 1 (IL-1) alters several potentially pathogenic endothelial cell (EC) functions. The authors report here that recombinant human IL-1 (rIL-1) alpha (0.1 to 10 ng/ml) or IL-1-beta (1 to 100 ng/ml) induce concentration- and time-dependent increases in IL-1-beta mRNA levels in EC derived from adult human saphenous vein. rIL-1 induced IL-1-alpha mRNA only in EC treated concomitantly with cycloheximide (2 micrograms/ml). IL-1-beta mRNA production began within 1 hr of exposure to rIL-1, peaked after 24 hr, and declined thereafter. Actinomycin D prevented the appearance of IL-1 mRNA in rIL-1-treated EC. rIL-1 also induced the release of biologically active IL-1 from EC, which was inhibited by cycloheximide (1 microgram/ml). When compared on the basis of their activity in the thymocyte costimulation assay, rIL-1-alpha and rIL-1-beta were equipotent as inducers of IL-1 production by EC. EC stimulated with rIL-1 produced prostaglandin E2, which inhibits IL-1 production by other cell types and also decreases the responsiveness of thymocytes to IL-1. When EC were exposed to rIL-1 in the presence of indomethacin (1 microgram/ml), which blocked prostaglandin E2 production, greater amounts of rIL-1-induced IL-1 release were detected, although the inhibitor did not affect IL-1-beta mRNA levels. IL-1-induced IL-1 production was unlikely to be caused by endotoxin contamination of tissue culture media or IL-1 preparations, because the lipopolysaccharide (LPS) antagonist polymyxin B (10 micrograms/ml) blocked LPS-induced IL-1 production by EC but did not affect IL-1 release in response to rIL-1-beta (100 ng/ml). The IL-1-inducing property of rIL-1-beta was heat-labile, whereas heated LPS stimulated EC IL-1 production. The source of IL-1 in our cultures was not monocyte/macrophages, as treatment of EC with monoclonal antibody to the monocyte antigen Mo2 under conditions that lysed adherent peripheral blood monocytes did not affect production of IL-1 by EC in response to LPS (1 microgram/ml) or rIL-1-beta (100 ng/ml). IL-1 elicits a coordinated program of altered endothelial function that increases adhesiveness for leukocytes and coagulability. IL-1-induced IL-1 gene expression in human adult EC could thus provide a positive feedback mechanism in the pathogenesis of vascular disease including atherosclerosis, vasculitis, and allograft rejection.
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PMID:Interleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cells. 349 83

Although the accumulation of monocyte-derived foam cells in the subendothelium is a key step in early atherogenesis, the mechanism responsible for monocyte adhesion to and subsequent transmigration through endothelial cells (ECs) has not been defined fully. We investigated the kinetics and the role played by adhesion molecules in the adhesion and transmigration of human monocytes using an in vitro three-dimensional model system comprising ECs cultured on collagen gels. Monocyte adhesion to untreated EC layers increased with time, reached a maximum after 3 h, and then declined. Monocyte transmigration through untreated EC layers also increased with time and reached a plateau after 3-4 h. Prestimulation of ECs with interleukin-1 beta (IL-1 beta; 25 U/ml) for 4 h enhanced monocyte adhesion (40.7 +/- 1.4%) and transmigration (37.9 +/- 1.6%) significantly compared with the value for untreated EC layers. In unstimulated EC layers, anti-leukocyte function-associated antigen-1 (LFA-1) plus anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibodies (mAbs) inhibited monocyte adhesion and transmigration significantly by 19% and 20%, respectively, whereas anti-very late antigen-4 (VLA-4) plus anti-vascular cell adhesion molecule-1 (VCAM-1) mAbs did not. In IL-1 beta-stimulated EC layers, anti-LFA 1 plus anti-ICAM-1 mAbs inhibited the adhesion and transmigration by 32% and 30%, respectively and anti-VLA-4 plus anti-VCAM-1 mAbs did so by 18% and 27%, respectively. These results suggest that the monocyte-EC interaction in unstimulated ECs is mediated, in part, by the LFA-1-ICAM-1 pathway and in IL-1 beta-stimulated ECs, in part, by both LFA-1-ICAM-1 and VLA-4-VCAM-1 pathways.
Atherosclerosis 1994 Jul
PMID:Involvement of adhesion molecules in human monocyte adhesion to and transmigration through endothelial cells in vitro. 752 75


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