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)

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

High level of fibrinogen in plasma is recognised as an important vascular risk factor. However, it is not known if the increase in fibrinogen is directly responsible for the vascular risk or is a marker of vascular inflammation. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since a parallel effect of cytokines on fibrinogen biosynthesis and on vascular injury was noted. Among the cytokines which induce the synthesis of fibrinogen, oncostatin M (OSM) is the most potent cytokine synthesised by activated monocytes for inducing fibrinogen synthesis by Hep G2 cells (human hepatoma cell line). Interestingly at the same concentrations needed for fibrinogen biosynthesis, OSM induces smooth muscle cell proliferation. In contrast, the cytokines IL-4, IL-10 and IL-13 which have a protective effect against vascular injury leading to atherosclerosis, dose dependently down regulate the biosynthesis of fibrinogen. This was due to both a decrease of IL-6 induced fibrinogen synthesis by hepatocytes, evidenced by a decrease in fibrinogen secretion in the medium and beta chain mRNA expression and to an inhibition of production of the hepatocyte-stimulating activity for fibrinogen biosynthesis (HSF) by LPS-activated monocytes. Noteworthingly, IL-10 induces a significant decrease of the production of OSM by LPS-activated monocytes. In situ activation of monocytes by cytokines in the vessel wall could also contribute to the deposition of fibrin(ogen) derivatives, identified as pathogenic factor.
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PMID:Regulation of fibrinogen biosynthesis by cytokines, consequences on the vascular risk. 897 38

There is considerable evidence to suggest that cytokines modulate the pathological cellular events that occur in human atherosclerosis. We sought to determine the effects of T-helper-lymphocyte (TH)-1- and TH2-type cytokines on the ability of human monocytes to oxidize LDL, one of the pathological processes believed to occur in atherosclerosis. The ability of opsonized zymosan (ZOP)-activated human monocytes to oxidize LDL in a 24-hour period was significantly enhanced by pretreatment of the monocytes with the TH2 cytokines, interleukin (IL)-4, or IL-13 compared with untreated monocytes. In contrast, interferon (IFN)-gamma, a TH1 cytokine, inhibited LDL oxidation by activated monocytes. Treatment with IFN-gamma also prevented the IL-4- and IL-13-mediated enhancement of LDL oxidation by ZOP-activated monocytes. Untreated or cytokine-treated unactivated monocytes did not oxidize LDL. The enhancement of LDL oxidation mediated by IL-4 or IL-13 treatment was not due to a mitogenic effect of the cytokines on the monocytes, nor to modulation of superoxide anion (O2-) production. The cytokine regulation of 15-lipoxygenase (LO) in the monocytes was also examined. IL-4 and IL-13 induction of 15-LO mRNA and 15-LO activity in the monocytes was confirmed, as was the previously reported inhibition of induction by IFN-gamma. In summary, IL-4 and IL-13 enhance the ability of activated human monocytes to oxidize LDL, whereas IFN-gamma inhibits the cell-mediated oxidation. The up- and downregulation of activated monocyte-mediated LDL oxidation by these cytokines correlates with the expression of 15-LO activity. Considerable evidence suggests that the progression of atherosclerosis includes events that are immunologically mediated, lending potential physiological relevance to these in vitro observations.
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PMID:Cytokine modulation of LDL oxidation by activated human monocytes. 935 59

1. The production of chemokines by vascular smooth muscle cells (SMC) is implicated in the pathogenesis of atherosclerosis, although the factors regulating chemokine production by these cells are incompletely characterized. 2. We describe the differential stimulation of interleukin-(IL)-8, monocyte chemoattractant protein (MCP)-1 and regulated on activation normal T-cell expressed and secreted (RANTES) synthesis following treatment of human vascular SMC with IL-1alpha or tumour necrosis factor alpha (TNFalpha). Under basal conditions, cultured SMC release very low amounts of IL-8, MCP-1 and RANTES as assessed by specific ELISA. Concentration-response studies with IL-1alpha or TNFalpha revealed that each stimulus induced a similar amount of MCP-1. In contrast approximately three fold more IL-8 was induced by IL-1alpha than by TNFalpha whereas significant RANTES production was induced only by TNFalpha. These findings point to a divergence in the regulation of synthesis of the different chemokines in response to IL-1alpha or TNFalpha stimulation. 3. The T-cell derived cytokines IL-10 and IL-13 were also found to have differential effects on chemokine production by SMC. IL-13, but not IL-10, significantly enhanced IL-8 and MCP-1 release in response to IL-1alpha or TNFalpha. This increase in chemokine release appeared to be accounted for by increased mRNA expression. 4. These findings provide support for the concept that smooth muscle cells can have an active role in a local immune response via the production of chemokines which can be selectively modulated by T-cell derived cytokines.
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PMID:Chemokine production by human vascular smooth muscle cells: modulation by IL-13. 937 73

Hyaluronectin (HN) is a component of the extracellular matrix of connective tissue and is particularly associated with tumour inflammatory and connective stroma reaction, where it co-localizes with hyaluronic acid (HA). The HN/HA ratio has been suggested to be involved in tumour aggressivity and in the atherosclerosis process. IL-10 has also been described in atherosclerotic lesions and in cancer. HN production was therefore investigated in vitro in peripheral blood monocyte cell (PBMC) cultures, with and without bacterial lipolysaccharide (LPS) or interleukins (ILs) in the medium. HN was characterized in monocytic cell cytoplasm and in culture supernatants. Anti-IL-10 antibody suppressed the LPS-stimulating effect on HN production. HN synthesis rate was greatly increased in IL-10-activated cultures while IL-4 and IL-13, two other anti-inflammatory ILs, decreased HN release. In the presence of IL-10, the IL-4 or Il-13 inhibitory effect on HN synthesis was reversed. The results support the view that intratumoral release of IL-10 by monocytes may induce local production of HN. In conjunction with the known ability of HN to bind to HA, which is a cell migration and tumour invasion facilitating factor, and to inhibit HA-induced angiogenesis, our findings suggest that HN may modulate the effect of HA on atherosclerosis, angiogenesis and cancer development.
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PMID:Hyaluronectin secretion by monocytes: downregulation by IL-4 and IL-13, upregulation by IL-10. 1043 4

The CD40-CD40 ligand (CD40L) system (CD154) is a central means of immune cell communication crucial for Ig class switching and enhanced Ag presentation. CD40 is also a key signaling conduit to activate nonhematopoietic cells, such as fibroblasts and endothelial cells, to produce proinflammatory mediators. Disruption of the CD40-CD40L pathway reduces lung inflammation and fibrosis, autoimmune disease and atherosclerosis. Non-bone marrow-derived structural cells are not known to express CD40L. In this study, we reveal the intriguing finding that primary strains of human lung fibroblasts derived from normal and scarred lung express both CD40L mRNA and protein. Interestingly, CD40L expression is down-regulated by IFN-gamma, a type 1 cytokine with antiscarring properties, and is up-regulated by the profibrogenic type 2 cytokine IL-13. Flow cytometry and laser confocal microscopy revealed that the majority of CD40L was located intracellularly. Importantly, fibroblast strains from human idiopathic pulmonary fibrosis tissue expressed increased levels of CD40L compared with fibroblasts from nonscarred lung. Fibroblasts in the scarred areas of human lung tissue expressed high levels of CD40L. Finally, the blood and lung lavage levels of CD40L are significantly elevated in fibrosis patients compared with normals. These new findings demonstrate that fibroblasts are a new source of CD40L and that those involved in scarring may have undergone a selected expansion for high CD40L expression. Moreover, the antifibrotic activity of IFN-gamma may involve the down-regulation of fibroblast CD40L levels. We speculate that fibroblast-derived CD40L plays a role in promoting fibroblast activation and possibly in interaction with CD40 bearing cells.
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PMID:Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by IFN-gamma and IL-13, and implications for fibrosis. 1473 71

Mortality in dialysis patients is greater than that in the general population across all age groups. The disparity in mortality is greatest among patients aged under 35 years. Chronic kidney disease (CKD) is associated with the malnutrition, inflammation and atherosclerosis (MIA) syndrome, which helps to explain the high mortality rates among patients with CKD. Paradoxically, CKD patients exhibit signs of immune suppression as well as immune system activation. Chronic inflammation and immune system activation are not only integral to the MIA syndrome, but also may underlie resistance to erythropoietin treatment in patients with anaemia. Chronic immune system activation is reflected by abnormally raised T-lymphocyte and monocyte expression of both pro- and anti-inflammatory cytokines. Patients who respond well to erythropoietin treatment exhibit fairly normal expression of these cytokines. Patients who persistently fail to respond, however, express abnormally raised levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), which are also known to inhibit erythropoiesis. Paradoxically, these patients also express abnormally high levels of the anti-inflammatory cytokines interleukin (IL)-10 and IL-13. Although anti-inflammatory in nature, these cytokines might also affect erythropoiesis. One strategy to overcome the problem of chronic inflammation in anaemic patients with CKD may be treatment with the phosphodiesterase inhibitor, pentoxifylline. Preliminary results suggest that once-daily treatment with 400 mg of pentoxifylline orally not only can reduce T-cell expression of TNF-alpha and IFN-gamma, but can also restore the response to erythropoietin and improve haemoglobin levels. Ongoing studies will investigate further the use of pentoxifylline in erythropoietin resistance.
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PMID:Could anti-inflammatory cytokine therapy improve poor treatment outcomes in dialysis patients? 1528 64

IL-4 and IL-13 are prototypic Th2 cytokines that generate an "alternatively activated" phenotype in macrophages. We used high-density oligonucleotide microarrays to investigate the transcriptional profile induced in human monocytes by IL-13. After 8-h stimulation with IL-13, 142 genes were regulated (85 increased and 57 decreased). The majority of these genes were related to the inflammatory response and innate immunity; a group of genes related to lipid metabolism was also identified, with clear implications for atherosclerosis. In addition to characteristic markers of alternatively activated macrophages, a number of novel IL-13-regulated genes were seen. These included various pattern recognition receptors, such as CD1b/c/e, TLR1, and C-type lectin superfamily member 6. Several components of the IL-1 system were regulated. IL-1RI, IL-1RII, and IL-1Ra were all up-regulated, whereas the IL-1beta-converting enzyme, caspase 1, and IRAK-M were down-regulated. LPS-inducible caspase 1 enzyme activity was also reduced in IL-13-stimulated monocytes, with a consequent decrease in pro-IL-1beta processing. These data reveal that IL-13 has a potent effect on the transcriptional profile in monocytes. The IL-13-induced modulation of genes related to IL-1 clearly highlights the tightly controlled and complex levels of regulation of the production and response to this potent proinflammatory cytokine.
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PMID:Transcriptional profiling reveals complex regulation of the monocyte IL-1 beta system by IL-13. 1590 89

The established risk factors for atherosclerosis fail to fully explain the extent and severity of coronary artery diseases in 50% of the patients. Thus, the causative agents and processes, which may be involved in the pathogenesis of atherosclerosis, are being sought. Notoriously, atherosclerosis and cardiovascular event rates are much lower in developing countries. Clinically, severe infections by intracellular pathogens are widespread mostly in developing countries with poor sanitation, nutrition and massive worm infections. A link between atherosclerosis and helminth infections has never been examined. Based on the present knowledge of immune and infectious mechanisms related to atherosclerosis, it is proposed that chronic helminthic infections can have a significant bearing on the epidemiology of cardiovascular diseases. How can helminthic infections affect the cardiovascular risk? (1) Helminths evade or suppress host immune responses, by producing anti-inflammatory and other immunomodulatory molecules. (2) Helminths induce chronic Th2 activation, which can modify cytokine profiles and immunological responses to heat shock proteins, Chlamydia pneumoniae and cytomegalovirus. (3) The chronic Th2 profile may modulate monocyte activation and chemotaxis to inflammatory sites (atherosclerotic plaques). (4) Chronic Th2 activation may lead to a cytokine profile that could be beneficial for attenuation of atherosclerosis development (upregulation of IL-4, IL-10 and IL-13 and downregulation of proinflammatory cytokines). (5) Helminthic infections may reduce plasma LDL level not only by affecting the host nutrition, but also via modulation of naturally occurring antibodies to cholesterol. Studies are needed to clarify these suggestions. If the hypothesis that helminthic infections impact atherosclerosis is correct, it should be taken into consideration in atherosclerosis immunomodulation therapy and especially in the design of vaccines and vaccine trials.
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PMID:Can worms defend our hearts? Chronic helminthic infections may attenuate the development of cardiovascular diseases. 1578 Apr 83

Atherosclerosis is generally considered an inflammatory disease characterized by the accumulation of lipid in large and medium elastic arteries. Individuals who smoke are at increased risk for developing atherosclerosis and the clinical events associated with this disease. Underlying the mechanisms involved in atherosclerotic lesion development exists a complex pattern of signaling, involving molecules (cytokines and chemokines) that mediate the progression of arterial lesions. The unique nature of exposure to tobacco-related toxicants during the process of smoking prompted our investigation of the time-dependent responses of two critical cell types to cigarette smoke condensate exposure. In this study, we examined the kinetic responses, using suspension array technology and RT-PCR of 17 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17 GM-CSF, G-CSF, INF-gamma, TNF-alpha, MCP-1 and MIP-1beta) in human aortic endothelial cells (HAECs) and THP-1 monocyte macrophages following exposure to cigarette smoke condensate (CSC) for 24h. In HAECs, IL-8 and IL-4 were rapidly stimulated by CSC exposure while, surprisingly, MCP-1 expression was downregulated. In THP-1 macrophages, IL-6, MIP-1beta, MCP-1 and IL-1beta protein expression were suppressed upon CSC exposure. All other measurable cytokines in THP-1 cells exposed to CSC had levels of protein and mRNA similar to controls. Depending on cell type, CSC uniquely influences the expression of cytokines. The complex interplay of these signaling molecules within the framework of atherosclerosis points to the ability of cigarette smoke components to alter such signaling following acute exposure, and by this mechanism may alter the course of both atherogenesis initiation and progression.
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PMID:Kinetic analysis of cytokine response to cigarette smoke condensate by human endothelial and monocytic cells. 1588 68


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