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 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

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

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.
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PMID:Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. 796 80

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

We recently reported that tumor necrosis factor alpha is able to cause a dose-dependent and persistent reduction in gap junctional intercellular communication between primary human smooth muscle cells. In order to study whether this observed persistent reduction in gap junctional intercellular communication is a unique feature for tumor necrosis factor alpha, the present study focuses on the effects of other growth factors and cytokines on gap junctional intercellular communication. Platelet-derived growth factor AA and BB (PDGF-AA, PDGF-BB), basic fibroblast growth factor (bFGF), interleukin-6 and interferon-gamma were able to modulate gap junctional intercellular communication between primary human smooth muscle cells in vitro. However, our results demonstrate that the magnitude and nature of the observed effects are growth factor- and cytokine-specific. PDGF-AA, PDGF-BB and interleukin-6 caused a transient reduction in gap junctional intercellular communication, while bFGF induced a transient increase in gap junctional intercellular communication. Interferon-gamma was shown to be capable of causing a persistent reduction in gap junctional intercellular communication. In addition, PDGF-AA, PDGF-BB, bFGF, interleukin-6, interferon-gamma and tumor necrosis factor alpha all stimulated smooth muscle cell proliferation. These observations suggest a more complex relationship between modulation of gap junctional intercellular communication and cell proliferation than current hypotheses imply. The implications of the observed effects of growth factors and cytokines on gap junctional intercellular communication between smooth muscle cells in relation to the process of atherosclerosis is discussed.
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PMID:Modulation of intercellular communication between smooth muscle cells by growth factors and cytokines. 888 70

Vascular endothelial cell (EC) costimulation of cytokine secretion by T lymphocytes may be important in inflammation and allograft rejection. Venous and arterial iliac endothelial cells (VIEC, AIEC) both costimulate interleukin-2 (IL-2) production by peripheral blood lymphocytes (PBL) or T cell clones stimulated with phytohemagglutinin (PHA). Interferon-gamma (IFN-gamma) production is costimulated in a subset of clones but IL-4 is not. Surprisingly, two T cell clones were reciprocally better costimulated by VIEC or AIEC. EC activation by pretreatment with tumor necrosis factor alpha (TNF-alpha) does not increase T cell costimulation despite large increases in EC cell adhesion molecule expression. Neither VIEC nor AIEC express CTLA4-binding molecules and costimulation is blocked by cyclosporin A, suggesting that CD28 is not involved in EC costimulation of T cells. These data suggest that adult vascular EC costimulate production of IL-2 and IFN-gamma but not IL-4 by mature T cells, that EC costimulation is not increased in inflamed tissues, and that different EC optimally costimulate particular T cells. These findings have implications for the nature of the costimulatory signal(s) provided by EC and may be important in understanding vasculitis or atherosclerosis.
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PMID:Arterial and venular endothelial cell costimulation of cytokine secretion by human T cell clones. 958 6

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon-gamma (IFN-gamma) contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule-1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the IFN-gamma-induced extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and IFN-gamma, ICAM-1 was expressed at a lower level than in cells treated with IFN-gamma alone. However, lovastatin does not reduce TNF-alpha induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-gamma. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the IFN-gamma activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit IFN-gamma-mediated induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the IFN-gamma-mediated phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. TNF-alpha does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting IFN-gamma action in atherosclerotic process
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PMID:Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. 1252 87

Macrophages play an important role in immune responses and in inflammatory disease states such as atherosclerosis. Interferon-gamma (IFN-gamma) is a major cytokine involved in the activation of macrophages. To elucidate the primary response of various genes and biological pathways regulated by IFN-gamma in macrophage, we analyzed the gene expression profile in RAW 264.7 macrophage cells treated with IFN-gamma for 4h. Microarray analysis revealed that about 400 genes were differentially expressed, of which about 250 genes were up-regulated and 150 were down-regulated. Functional organization of the transcriptome revealed that induced genes are involved in antimicrobial and antiviral responses, antigen presentation, chemokine and cytokine signaling, and inhibition of cell growth. We also found that expression of genes involved in cell-cycle control, DNA repair, and lipid metabolism was suppressed by IFN-gamma. We also identified induction of multiple transcription factors by IFN-gamma in RAW 264.7 cells. Functional annotation of genes regulated by IFN-gamma in RAW 264.7 cells may provide novel insights into the role of macrophages in immunity and in inflammatory disease.
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PMID:Regulation of gene expression in RAW 264.7 macrophage cell line by interferon-gamma. 1651 65

Inflammatory processes contribute to the pathogenesis and complications of atherosclerosis and coronary heart disease (CHD). Several findings indicate that chlamydial heat shock proteins (HSP) may represent a particularly strong antigenic stimulus, able to induce specific humoral (Ab) and T-cell-mediated immune responses (CMI) linking infection by Chlamydia pneumoniae (CP) to immuno-pathological sequelae such as atherosclerosis and CHD. We have here evaluated the ability of chlamydial recombinant (r) HSP60 and rHSP10 to induce specific immune responses in human peripheral blood lymphocytes and in murine models. rHSP60, but not rHSP10, was shown to induce proliferation and Interferon-gamma secretion in lymphocytes of randomly selected blood donors, as well as to generate and detect delayed-type hypersensitivity response in HSP60-vaccinated mice. Overall, the present study provides new hints to evaluate a previous exposition to CP using rHSP60 in humans. Thus the evaluation of specific HSP60 CMI response in healthy subject could be useful to monitor the reactivity to Chlamydia pneumoniae possibly providing a link to CHD pathologies.
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PMID:60-kDa heat shock protein of Chlamydia pneumoniae is a target of T-cell immune response. 1660 28

Inflammation and immune activation are crucially involved in the pathogenesis of atherosclerosis and cardiovascular disease. Accordingly, markers of inflammation such as fibrinogen, ferritin, C-reactive protein or neopterin are found in patients with vascular diseases, correlating strongly with the extent of disease and predicting disease progression. Neopterin formation by human monocyte-derived macrophages and dendritic cells is induced by the pro-inflammatory cytokine interferon-gamma, which is released by activated T-lymphocytes. Human macrophages are centrally involved in plaque formation, and interferon-gamma and macrophages are also of importance in the development of oxidative stress for antimicrobial and antitumoural defence within the cell-mediated immune response. Interferon-gamma also stimulates the enzyme indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine. Again, macrophages are the most important cell type executing this enzyme reaction, but also other cells like dendritic cells, endothelial cells or fibroblasts can contribute to the depletion of tryptophan. Likewise, enhanced tryptophan degradation was reported in patients with coronary heart disease and was found to correlate with enhanced neopterin formation. In chronic diseases such as in cardiovascular disease, biochemical reactions induced by interferon-gamma may have detrimental consequences for host cells. In concert with other pro-inflammatory cytokines, interferon-gamma is the most important trigger for the formation and release of reactive oxygen species (ROS). Chronic ROS-production leads to the depletion of antioxidants like vitamin C and E and glutathione, with a consequence that oxidative stress develop. Oxidative stress plays a major role in the atherogenesis and progression of cardiovascular disease, and it may also account for the irreversible oxidation of other oxidation-sensitive substances like B-vitamins (e.g. folic acid and B12). They are essential cofactors in homocysteine-methionine metabolism. Associations between moderate hyperhomocysteinaemia and cellular immune activation are found in several diseases including coronary heart disease, and data indicate that hyperhomocysteinaemia may develop as a consequence of immune activation. Homocysteine accumulation in the blood is established as an independent risk factor for cardiovascular disease. Homocysteine itself has the capacity to further enhance oxidative stress. Interferon-gamma appears to be a central player in atherogenesis and in the development and progression of cardiovascular disease. Anti-inflammatory and immunosuppressive treatment (e.g. with non-steroidal anti-inflammatory drugs or statins) may among other consequences, also contribute to a slow-down of the adverse effects of interferon-gamma.
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PMID:Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease. 1684 38


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