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)

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

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

Effect of interleukin 4 (IL-4) on the production of matrix metalloproteinase 1 (MMP-1) by normal and immortalized human intimal smooth muscle cells (SMC) was investigated. The production of the precursors of MMP-1 by intimal SMC was enhanced in a dose-dependent manner by addition of IL-4 to the culture medium, whereas the cytokine also showed an inhibitory effect on DNA synthesis in the cells. In addition, mRNA of IL-4 was found in the atherosclerotic and nonatherosclerotic areas of the intima. Although the production of MMP-1 and the proliferation of SMC are thought to play an important role in reconstruction of the intima during atherogenesis, our results suggest a possible role of IL-4 induced MMP-1 in inhibiting tissue remodeling caused by a variety of arterial disorders including atherosclerosis.
Atherosclerosis 1998 Jun
PMID:A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells. 969 Sep 7

Lysophosphatidylcholine (lyso-PC) accumulates in tissues undergoing inflammation and atherosclerosis, where an infiltration of T cells is also seen. We found that lyso-PC increased IFN-gamma production and CD40L expression in CD4+ T cells stimulated with anti-CD3 Ab and recombinant CD80 molecules, whereas lyso-PC did not affect IL-2 and IL-4 production. These results suggest that lyso-PC, in combination with other stimuli, may regulate CD4+ T cell functions to propagate local inflammatory reactions and also imply a novel role played by a modified lipid in the selection of Th1/Th2 immune response as well as in the T cell mediated pathogenesis in atherosclerosis.
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PMID:Lysophosphatidylcholine upregulates CD40 ligand expression in newly activated human CD4+ T cells. 973 53

The cytokine profile of atherosclerotic aortas from apoE-deficient mice was assessed by reverse transcriptase-polymerase chain reaction. The results clearly showed that the expression of mRNA for IL-12p40 was evident in aortas from 3-month-old apoE-deficient mice. The mRNA for IL-10 was detected in aorta from these mice at the age of 6 months, indicating that expression of IL-12 is earlier than that of IL-10 in these animals. Concurrent with IL-12p40, the mRNA for the T-cell cytokine IFN-gamma, but not IL-4, was detected in aortas of mice at young and old ages. Both in situ hybridization and immunostaining further demonstrated the localization of IL-12 in macrophages of atherosclerotic lesions. Immunohistochemistry also demonstrated the expression of costimulatory molecules B7-1 and B7-2 in macrophages, suggesting that activation of T lymphocytes by macrophages may occur via surface antigens in lesions. When the immunoglobulin isotype of the antioxidized LDL antibodies in sera of apoE-deficient mice was determined, it revealed that both IgM and IgG were present. Furthermore, IgG2a is predominant and comprises approximately 50% of the antioxidized LDL IgG in sera from young mice (3 months), but decreased to lower levels (35%) in older mice (6 months). Daily administration of IL-12 led to an increase in serum levels of antioxidized LDL antibodies and accelerated atherosclerosis in young apoE-deficient mice compared with control mice injected with PBS alone. Taken together, these data suggest that IL-12 plays an active role in regulating the immune response during the early phase of atherosclerosis in apoE-deficient mice.
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PMID:The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. 1007 81

T cells take part in the chronic inflammatory reaction in atherosclerotic plaques, but their specific role in atherosclerosis has not yet been fully elucidated. Nevertheless, one may anticipate that activated T cells may secrete cytokines capable of modulating the morphology and hence the stability of plaques by regulating cell proliferation, lipid metabolism, and extracellular matrix (ECM) synthesis and/or degradation. This study has been designed to investigate the functional properties of T cells in atherosclerotic lesions. For this purpose, T-cell clones were generated from atherosclerotic plaques isolated from human aortas obtained at autopsy from six subjects. Cloned cells were activated with PMA and OKT-3 to initiate cytokine production and cytokine profiles of CD4-positive clones were measured by ELISA. The majority of the T-cell clones (125/155, 81 per cent) produced both interferon (IFN)-gamma and interleukin (IL)-4 (type 0 cytokine profile). Moreover, the production of IFN-gamma was dominant in the majority of these clones. A type 1 cytokine profile (high levels of IFN-gamma and low levels of IL-4) was found in 17 per cent of the clones (27/155). Only three clones (2 per cent) showed a type 2 cytokine secretion pattern (high levels of IL-4 and low levels of IFN-gamma). No cytolytic activity could be established in plaque-derived T cells. Our results show that the T-cell population in atherosclerotic lesions is heterogeneous, but the most dominant T cell by far is the one with a type 0 cytokine profile. The dominant secretion of IFN-gamma by T-cell clones suggest an important role for plaque T cells in modulating the growth and differentiation of other cells, such as macrophages and smooth muscle cells in atherosclerotic plaques.
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PMID:Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic plaques. 1039 61

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

Human 12/15-lipoxygenase is a lipid-peroxidating enzyme implicated in the pathophysiology of atherosclerosis and airway inflammation. Interleukin (IL)-4 specifically induces 12/15-lipoxygenase messenger RNA, protein, and enzymatic activity in primary cultures of human monocytes and airway epithelial cells. The induction of the human 12/15-lipoxygenase by IL-4 suggests that the signal transducer and activator of transcription (Stat)-6 protein is critical for its expression. Several putative Stat6 response elements are located in the proximal 1.8 kb of 12/15-lipoxygenase 5'-flanking region. In this study we use BEAS-2B human airway epithelial cells as a model to demonstrate the dependence of 12/15-lipoxygenase expression on the IL-4/Stat6 signal transduction pathway. Transient transfections of human 12/15-lipoxygenase promoter/luciferase reporter genes indicate that this induction occurs through direct transcriptional mechanisms mediated by a specific Stat6 response element located 952 base pairs upstream of the translational start codon. Using this Stat6 response element as a probe, electrophoretic mobility shift assays show an IL-4-dependent binding activity in nuclear extracts. Supershift assays confirm that Stat6 participates in this binding complex. These data indicate that the human 12/15-lipoxygenase gene is induced in airway epithelial cells through Stat6-dependent transcriptional mechanisms mediated by a specific Stat6 response element in the 5'-flanking region.
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PMID:Regulation of human 12/15-lipoxygenase by Stat6-dependent transcription. 1065 44

Atherosclerotic lesions can be induced in rabbits and mice immunized with heat shock protein 65 (HSP65). In the current study, we investigated the role of interleukin (IL)-4 in the HSP65- and Mycobacterium tuberculosis (MT)-induced models that exhibit an inflammatory phenotype. Fatty streak formation in IL-4-knockout (IL-4 KO) mice immunized with HSP65 or MT was significantly reduced when compared with lesions in wild-type C57BL/6 mice. However, when injected with control (HSP-free) adjuvant, no differences were evident in the lesion size between wild-type and the IL-4 KO mice. Next, we studied comparatively the extent of humoral and cellular immune responses to HSP65 in the IL-4 KO and wild-type mice, as those are thought to be influential in murine atherosclerosis. Anti-HSP65 antibody levels were reduced in the HSP65-immunized IL-4 KO mice as compared with their wild-type littermates, whereas no differences were evident between the groups with respect to the primary cellular immune response to HSP65. Other than the absence of IL-4 in the knockout mice, the pattern of secreting cytokines interferon-gamma and IL-10 in concanavalin A-primed splenocytes was similar between the groups. HSP65-primed inguinal lymphocytes from IL-4 KO mice immunized with HSP65 secreted higher levels of interferon-gamma (previously shown to be proatherogenic in vivo) as compared with their wild-type controls. 12-/15-Lipoxygenase expression, known to be regulated by IL-4 and to contribute to murine atherosclerosis, in the lesions was not influenced by the immunization protocol used or by IL-4 disruption. Thus, IL-4 may prove a principal cytokine in the progression of early "inflammatory" atherosclerotic lesions and may serve as a target for immunomodulation.
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PMID:Requisite role for interleukin-4 in the acceleration of fatty streaks induced by heat shock protein 65 or Mycobacterium tuberculosis. 1086 9

Oxygen free radicals as well as immunological reactions have been suggested to play important roles in atherogenesis and other pathological processes of the blood vessel wall. We have previously shown that the vascular wall contains exceptionally large amounts of extracellular superoxide dismutase (EC-SOD) and that the enzyme is produced and secreted to the extracellular space by the smooth muscle cells. In this work, we studied the influence of inflammatory cytokines on vascular smooth muscle cell expression of EC-SOD, the mitochondrial manganese superoxide dismutase (Mn-SOD) and the cytosolic copper zinc superoxide dismutase (CuZn-SOD). The expression of EC-SOD was up-regulated by interferon-gamma (IFN-gamma) and interleukin 4 (IL-4). and was down-regulated by tumor necrosis factor-alpha (TNF-alpha). The ratio between the maximal stimulation and depression observed was around 20-fold. The responses were slow and developed over periods of several days. The Mn-SOD activity was strongly up-regulated by TNF-alpha and IL-1alpha and moderately by IFN-gamma. The CuZn-SOD activity of the smooth muscle cells was not significantly influenced by any of the cytokines. The findings suggest that large changes in the SOD isoenzymes might occur in vascular diseases, significantly altering the susceptibility of the vascular wall to adverse effects of the superoxide radical.
Atherosclerosis 2000 Aug
PMID:Multiple cytokines regulate the expression of extracellular superoxide dismutase in human vascular smooth muscle cells. 1092 20


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