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)

The early stages of atherosclerosis are characterized by penetration into the arterial intima by both T lymphocytes and monocytes. Some of these T lymphocytes show signs of activation, though the mechanisms by which they become activated are not known. The monocytes develop into macrophages and subsequently into foam cells filled with oxidized LDL (oxLDL)-derived lipids. OxLDL has been found to exert several proinflammatory effects, including enhanced adhesiveness of endothelial cells and monocytes, chemotaxis of monocytes and T cells, and T-cell activation. The enzyme-linked immunospot (ELISPOT) assay has been shown to be a sensitive method for detection of single cells secreting antibodies or cytokines. Here we have used this method to characterize the T-cell cytokine secretion pattern after exposure to oxLDL in vitro. In peripheral blood mononuclear cells from healthy donors (n = 27), a significantly enhanced number of INF-gamma-producing cells was detected by ELISPOT (P < .001) after stimulation with 5 micrograms/mL oxLDL. In contrast, production of interleukin-4 was not significantly enhanced after stimulation with oxLDL. OxLDL-induced IFN-gamma secretion and T-cell proliferation were completely inhibited by major histocompatibility complex (MHC) class II antibodies. Furthermore, oxLDL was found to enhance the antibody secretion, indicating B-cell activation. Our results indicate that oxLDL activates T cells by an MHC class II-dependent mechanism. In healthy individuals, oxLDL induces IFN-gamma, which is produced by T helper type 1-like cells. These findings demonstrate that oxLDL induces a cell-dependent immune reaction, which may play an important role in the development of atherosclerosis.
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PMID:Oxidized LDL induces enhanced antibody formation and MHC class II-dependent IFN-gamma production in lymphocytes from healthy individuals. 758 30

Although proliferation of smooth muscle cells is a key event in the pathogenesis of atherosclerosis, the signals which regulate this proliferation are not fully understood. It is likely that proliferation is regulated by cytokines released by cells found in the plaque, such as T cells. In this study we report that the T cell-derived cytokine, interleukin-4 (IL-4), can inhibit proliferation of cultured human umbilical artery smooth muscle cells. Maximum inhibitory effect was achieved at IL-4 concentrations of 20 U/ml or greater. In addition, the data showed that IL-4 acted early in the G1 phase of the cell cycle, thereby preventing cells from entering S phase. The mechanism of IL-4 inhibition did not appear to involve stimulation of prostanoid synthesis since similar data were obtained when experiments were performed in the presence of a cyclooxygenase inhibitor. We propose that IL-4 may act as a protective factor released by T-cells in an atherosclerotic lesion in order to minimise the size of the plaque.
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PMID:Interleukin-4 inhibits human smooth muscle cell proliferation. 779 23

Arachidonate 15-lipoxygenase (15-lipoxygenase) is a lipid-peroxidizing enzyme associated with specific inflammatory cells seen in asthma and atherosclerosis. In atherosclerosis, 15-lipoxygenase is induced in the macrophages of human and rabbit lesions and has been implicated in foam cell formation. In human lung, 15-lipoxygenase is preferentially expressed in airway epithelial cells and eosinophils. Our studies have focused both on the regulation of expression and on the structure-function relationships of the enzyme. To determine factors that could regulate expression, peripheral blood monocytes were purified and cultured with combinations of 18 factors. Only interleukin-4 (60 pM) induced 15-lipoxygenase mRNA, protein and enzymatic activity. Interferon-gamma (100 pM) inhibited the interleukin-4 dependent induction of 15-lipoxygenase. Results with cultured human airway cells were similar. These data suggest that expression of 15-lipoxygenase is regulated by interleukin-4, and that 15-lipoxygenase is a potential downstream effector molecule for this potent cytokine. In parallel studies, we have investigated determinants of positional specificity using site-directed mutagenesis and bacterial expression of human 15-lipoxygenase. Hypotheses for mutagenesis were derived from an analysis of conserved differences among multiple lipoxygenase sequences. Switching four amino acids in 15-lipoxygenase to their counterparts in 12-lipoxygenase resulted in a variant enzyme that produced equal 12- and 15-lipoxygenation. Further analysis has identified two amino acids that completely control the positional specificity of 15-lipoxygenase. These data have led to a preliminary model of the enzyme's active site region.
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PMID:Human 15-lipoxygenase: induction by interleukin-4 and insights into positional specificity. 835 18

High levels of fibrinogen are recognized as an important vascular risk factor; however, it is not known if the increase of plasma fibrinogen is directly responsible for this risk, or is only a marker of vascular inflammation. To support this second hypothesis, Oncostatin M (OSM) is a potent stimulator of fibrinogen biosynthesis and induces smooth muscle cell proliferation. In the same way, we analysed whether interleukin-4 (IL-4), interleukin-10 (IL-10) or interleukin-13 (IL-13), which protect vessel walls from monocytes injuries leading to atherosclerosis, could influence fibrinogen biosynthesis. The two levels of regulation of fibrinogen biosynthesis were tested: firstly, the direct effect of these cytokines on fibrinogen production by the hepatoma cell line Hep G2, and secondly their effect on the secretion of hepatocyte stimulating factor (HSF) activity in the supernatant of lipopolysaccharide (LPS)-activated monocytes. IL-4 and IL-13 added to Hep G2 cells down-regulated both the increase of fibrinogen secretion induced by IL-6 and fibrinogen mRNA levels, this effect being more pronounced when Hep G2 were preincubated with the two cytokines before IL-6 addition. The effect of IL-10 was evidenced only on mRNA expression. IL-10 and IL-13 dose-dependently decrease HSF activity secreted by LPS-activated monocytes, whereas IL-4 had no effect. However, the three cytokines decreased HSF activity when monocytes were incubated with the cytokines before LPS activation. The effects of these cytokines on HSF activity are related to variations of IL-6 and OSM secretion. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since cytokines which have a protective vascular effect down-regulate fibrinogen production.
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PMID:Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13. 870 33

Induction of endothelial adhesion molecules by the cytokine tumor necrosis factor-alpha (TNF) can occur independently of protein kinase C and activation of a protein tyrosine kinase (PTK) has recently been implicated in the upregulation of vascular cell adhesion molecule 1 (VCAM-1) by interleukin-4 (IL-4) on endothelial cells. We demonstrate that the PTK inhibitors herbimycin A or genistein suppress induction of endothelial VCAM-1 and E-selectin, as well as subsequent monocytic cell adhesion to endothelial cells stimulated by TNF. Inhibition studies indicate that specific tyrosine phosphorylation following PTK activation is involved in the mobilization of the transcription factor, nuclear factor kappa B, and VCAM-1 mRNA expression. This may have implications for pathophysiological conditions that involve the upregulation of these molecules (e.g. inflammation and atherosclerosis).
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PMID:Involvement of tyrosine phosphorylation in endothelial adhesion molecule induction. 873 63

The action of an omega-6 lipoxygenase (LO) has been implicated in the development of atherosclerosis through a mechanism involving oxidation of LDL, and its regulation in macrophages may have important implications for the disease process. Human monocyte-derived macrophages (HMDMs) showed no demonstrable LO protein or activity unless they were incubated with interleukin-4 (IL-4). In contrast, mouse peritoneal macrophages (MPMs) possessed significant basal levels of LO activity and protein that were augmented by IL-4 treatment. Interferon gamma prevented the induction of LO in both HMDMs and MPMs. Whereas interferon gamma could completely block the IL-4 induction of LO in human cells, it did not suppress basal LO activity in MPMs. Both HMDMs and MPMs exhibited similar concentration-response relationships for stimulation of LO activity and protein, with maximal induction at 1 ng/mL IL-4. The time course of IL-4 induction of LO activity was markedly different in human and murine cells. IL-4 induced LO activity and protein in human cells by 48 hours that were maximal by 72 hours; there was a decline to a new baseline by 96 hours. MPMs have a significant amount of LO activity at baseline, which declined with time by nearly 10-fold in the absence of IL-4, IL-4 blunted the decline of LO activity with time and restored activity to that found at baseline by 48 hours. IL-4 was not responsible for the LO activity present in freshly isolated MPMs since both activity and protein content were similar in cells harvested from IL-4+/+ and IL-/- mice. Therefore, whereas IL-4 may be an important modulator of LO production in vitro, it is not essential for the in vivo expression of this protein. Further, these studies demonstrate that significant differences exist between monocyte-derived macrophages matured in vitro and tissue macrophages that have matured in vivo.
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PMID:Mouse peritoneal macrophages contain abundant omega-6 lipoxygenase activity that is independent of interleukin-4. 897 53

15-lipoxygenase is a lipid-peroxidating enzyme that oxidizes fatty acids, such as those esterified to cellular membranes. It has been implicated in the oxidative modification of low-density lipoprotein and is thus thought to contribute to the development of atherosclerosis. The enzyme has also been shown to be specifically induced by interleukin-4 in human blood monocytes. Two 15-lipoxygenase-hybridizing messages were detected in these cells; one (2.7 kb) corresponds to the previously isolated cDNA for 15-lipoxygenase, while the other (4 kb) was of unknown origin. We have isolated and characterized this 4 kb transcript. Our experiments show that it has 1.2 kb additional sequence in its 3' untranslated region, and that it is generated from genomic sequences through differential polyA site selection. We present studies to address the functional significance of the extended 3'UTR. Selection of an upstream polyadenylation signal results in production of the 2.7 kb transcript. In addition, we present here for the first time the cloning and sequence of the human 15-lipoxygenase gene, as well as the identification of regulatory elements in the promoter region of this gene.
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PMID:Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene. 922 51

Smooth muscle cell proliferation is a key event in the development of atherosclerosis. Inhibition of this proliferation may lead to better prevention and treatment of the disease. While a number of agents have been found to inhibit SMC proliferation, their mechanisms of action are not fully understood. We wanted to determine the effects of three physiologically relevant anti-mitogenic agents on two classes of proteins which have major roles in cellular proliferation, namely cyclins and cyclin-dependent kinases (cdks). Following stimulation with fetal calf serum (FCS), quiescent human umbilical artery smooth muscle cells (HUASMC) synthesised cyclin D1 mRNA and protein and cdk2 mRNA in the G1 phase, whereas cdc2 protein was expressed after the onset of the S phase. Heparin, a strong inhibitor of HUASMC proliferation, strongly down-modulated the levels of cyclin D1 mRNA and protein, cdk2 mRNA and cdc2 protein. Interleukin-4 (IL-4) or 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) also lowered the levels of these cell cycle regulatory proteins, although their effects were relatively weak, reflecting their only partial inhibition of HUASMC DNA synthesis. There was specificity in the cell cycle targets of the agents since none appeared to affect the levels of cdk4 protein.
Atherosclerosis 1997 Aug
PMID:G1 phase arrest of human smooth muscle cells by heparin, IL-4 and cAMP is linked to repression of cyclin D1 and cdk2. 925 8

Atherosclerosis is an inflammatory-fibrotic response to accumulation of cholesterol in the artery wall. In hypercholesterolemia, low density lipoproteins (LDL) accumulate and are oxidized to proinflammatory compounds in the arterial intima, leading to activation of endothelial cells, macrophages, and T lymphocytes. We have studied immune cell activation and the autoimmune response to oxidized LDL in atherosclerotic apo E-knockout mice. Autoantibodies to oxidized LDL exhibited subclass specificities indicative of T cell help, and the increase in antibody titers in peripheral blood was associated with increased numbers of cytokine-expressing T cells in the spleen. In addition to T cell-dependent antibodies, IgM antibodies to oxidized LDL were also increased in apo E-knockout mice. This suggests that both T cell-dependent and T cell-independent epitopes may be present on oxidized LDL. In moderate hypercholesterolemia, IgG antibodies were largely of the IgG2a isotype, suggesting that T cell help was provided by proinflammatory T helper (Th) 1 cells, which are prominent components of atherosclerotic lesions. In severe hypercholesterolemia induced by cholesterol feeding of apo E-knockout mice, a switch to Th2-dependent help was evident. It was associated with a loss of IFN-gamma-producing Th1 cells in the spleen, whereas IL-4-producing Th2 cells were more resistant to hypercholesterolemia. IFN-gamma but not IL-4 mRNA was detected in atherosclerotic lesions of moderately hypercholesterolemic apo E-knockout mice, but IL-4 mRNA appeared in the lesions when mice were made severely hypercholesterolemic by cholesterol feeding. These data show that IFN-gamma-producing Th1 cells infiltrate atherosclerotic lesions and provide T cell help for autoimmune responses to oxidized LDL in apo E-knockout mice. However, severe hypercholesterolemia is associated with a switch from Th1 to Th2, which results not only in the formation of IgG1 autoantibodies to oxidized LDL, but also in the appearance of Th2-type cytokines in the atherosclerotic lesions. Since the two subsets of T cells counteract each other, this switch may have important consequences for the inflammatory/immune process in atherosclerosis.
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PMID:Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice. 954 3

Chronic upregulation of P-selectin expression on the surface of the endothelium has been observed in and likely contributes to a number of chronic inflammatory diseases, including atherosclerosis. Agonists of P-selectin expression fall into 2 categories: those that induce a very rapid, transient increase, lasting only hours, and those that induce prolonged upregulation lasting days. It is the latter group, which includes interleukin-4 (IL-4), that is likely to be a mediator of chronic P-selectin upregulation. The increase in P-selectin expression induced by IL-4 results from increased transcriptional activation of the P-selectin gene. The aim of this study was to deduce the postreceptor signaling pathway(s) giving rise to the prolonged increase in P-selectin expression induced by IL-4. We demonstrate the existence of 2 functional signal transducer and activator of transcription 6 (Stat6) binding sites on the P-selectin promoter and further demonstrate, by functional analysis of the P-selectin promoter, that binding of activated Stat6 to at least 1 site is essential for IL-4-induction of P-selectin transcription. Site 1 (nucleotide[nt] -142) bound Stat6 with a higher affinity than did site 2 (nt -229), and this difference was reflected functionally as constructs in which only site 1 was functional showed full IL-4 inducibility, whereas constructs in which only site 2 was functional showed only 40% of maximal IL-4 inducibility. IL-4 also induced prolonged activation of Stat6, which was contingent on the continuous presence of IL-4. The sustained activation of Stat6 induced by IL-4 is likely to be a key factor leading to the prolonged activation of the P-selectin promoter, thereby resulting in prolonged P-selectin upregulation.
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PMID:Stat6 activation is essential for interleukin-4 induction of P-selectin transcription in human umbilical vein endothelial cells. 1036 72


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