Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this article is to review the pathogenetic factors of Alzheimer's disease. Primary correlates of Alzheimer's disease are a dysfunction of and a subsequent decrease in the number of cortical and hippocampal synapses, followed by neurofibrillary and neuritic changes of hippocampal and cortical neurons. While the synapse pathology has been shown to be an early event in Alzheimer's disease, a significant neurofibrillary and neuritic pathology appears to develop only during the course of the disease. Cortical amyloid deposits are an unspecific, age-related phenomenon that can also be found in the brains of the majority of nondemented elderly persons over the age of 65 years. Transgenic amyloid mice proved to be of only limited value as animal models of Alzheimer' disease. According to several studies, there is no correlation between the total number of cortical amyloid plaques and clinical parameters of dementia. However, such a correlation exists with respect to the proportion of neuritic plaques, i.e., with respect to the degree of neuritic degeneration within plaques. In addition to these changes, an interleukin-6 associated inflammatory response has been found in the cortices of Alzheimer patients which is absent in the brains of nondemented elderly persons, and which therefore appears to be a specific element. The significance of changes in the cholinergic neurotransmission for Alzheimer's disease is discussed. Finally, the role of apolipoprotein E and other genetic risk factors is reviewed. In this context it is emphasized that in young persons apolipoprotein E4 is not a suitable early diagnostic marker for Alzheimer's disease.
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PMID:[Pathogenetic factors of Alzheimer disease]. 766 89

Human apolipoprotein E is a plasma lipoprotein that appears to play an important protective role in the development of atherosclerosis. While little is known about the regulation of apoE, recent studies have shown that cytokines repress apoE synthesis both in vivo and in vitro. Furthermore, we have recently shown that the endogenous apoE gene is negatively regulated by the nuclear trans-repressor BEF-1 in the human HepG2 cell line. In this study we demonstrate that treatment of HepG2 cells with the cytokine interleukin-1 and interleukin-6 resulted in the induction of an isoform of BEF-1, designated B1. The induction of the B1 isoform could be blocked by the protein kinase inhibitor staurosporine, suggesting that B1 is a phosphorylated form of BEF-1. As further support, the B1 isoform could also be induced by phorbol ester, and subsequently inhibited by staurosporine, implicating a role for protein kinase C-mediated phosphorylation. Quantitation of the levels of the BEF-1 isoforms, and studies in the presence of cyclohexamide, provided evidence for the phosphorylation of an existing intracellular pool of BEF-1, with no change in the total intracellular level. Under conditions that generated increased levels of the B1 isoform, there was a concomitant and proportional decrease in the level of apoE mRNA. The effect did not appear to be the result of improved binding to the apoE regulatory region as the DNA binding affinity of B1 was identical to native BEF-1. Our data suggest that the regulation of apoE by BEF-1 is modulated by differential phosphorylation, possibly through the protein kinase C pathway.
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PMID:Trans-repressor BEF-1 phosphorylation. A potential control mechanism for human ApoE gene regulation. 861 16

Increased levels of interleukin-6 (IL-6) have been proposed to contribute to a number of pathological disorders, including osteoporosis and Alzheimer's disease. In human atherosclerotic lesions, IL-6 protein and mRNA have been detected, although the role of IL-6 in plaque formation is unknown. We have examined the expression pattern of IL-6 mRNA and secreted protein in male apolipoprotein E-knockout (apoE-KO) mice aortas. Furthermore, we have evaluated the effects of 17beta-estradiol (E2), a vasculoprotective sex steroid hormone, on the secretion of this inflammatory cytokine from isolated male apoE-KO mice aortas. The expression of IL-6 mRNA was detected by reverse transcription-polymerase chain reaction in the apoE-KO mouse aortas but not in the aortas of age-matched control mice. Similarly, the secretion of IL-6 protein from isolated apoE-KO aortic segments was significantly greater than that from aortas of age-matched control animals. The secretion of IL-6 from isolated aortic rings of apoE-KO mice ranging in age from 6 to 48 weeks showed a significant, positive correlation with percent lesion area measured in the same tissue. Immunohistochemical staining of apoE-KO mouse aortic tissue sections demonstrated colocalization of IL-6 expression with macrophages. Treatment of male apoE-KO mice with E2 for 3 weeks resulted in a statistically significant 50% reduction in IL-6 secretion from ex vivo aortic tissue segments. There was no significant change in total serum cholesterol and triglyceride levels in the E2-treated group compared with placebo-treated controls. These data demonstrate that (1) IL-6 mRNA and protein are expressed in the atherosclerotic plaques of apoE-KO mice aortas and (2) IL-6 production is suppressed by E2 treatment, which may contribute to the antiatherosclerotic effects of E2 in the apoE-KO mouse model of atherosclerosis.
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PMID:Expression of interleukin-6 in atherosclerotic lesions of male ApoE-knockout mice: inhibition by 17beta-estradiol. 974 40

Atherosclerosis, the main lethal disease in the Western world, is associated with a cellular immune response in the arterial lesions and a humoral immune response directed towards oxidized lipoproteins, certain microbes and other antigens. The local immune response is dominated by macrophages and T cells, while to date, the role of B cells in lesions has been unclear. We analysed B-cell involvement in lesions using the apolipoprotein E knockout mouse, an experimental model that develops accelerated atherosclerosis when fed a lipid-rich diet. Both early fatty-streak-type lesions and full-blown atherosclerotic plaques of these mice contained CD22+ B cells. They accumulated predominantly in the base of lesions, where high expression levels of vascular cell adhesion molecule-1 (VCAM-1) were observed in other cells. Cells expressing interleukin-6 and tumour necrosis factor-alpha were also detected and IgM was abundant in this region. These data show that B cells participate in atherosclerosis in this experimental model; the data also suggest that these cells may accumulate through VCAM-1 expression by surrounding cells and may produce antibodies and proinflammatory cytokines. These factors are likely to be important in the pathogenesis of atherosclerosis.
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PMID:Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein E knockout mice. 1040 48

A genetic contribution to bone mass determination was first described in the early 70s. Elucidation of gene contribution to this has since been attempted through studies analyzing associations between bone mass acquisition and/or maintenance and polymorphic variations of several genes. The first to be described was the vitamin D receptor gene (VDR), initially claimed to contribute to almost 75% of the genetic variation in bone mineral density (BMD) in twin and general population studies. Not all of the studies published to date conclude that a clear relationship exists between polymorphic VDR alleles and BMD, and the molecular basis for the VDR gene polymorphisms influence on bone mineralization has not yet been clarified. Since then, other genes with a significant role in bone metabolism such as estradiol receptor, collagen type 1alpha1, TGF-beta1, interleukin-6, calcitonin receptor, alpha2-HS-glycoprotein, osteocalcin, calcium-sensing receptor, interleukin-1 receptor antagonist, beta3-adrenergic receptor, apolipoprotein E, PTH, IGF-I and glucocorticoid receptor have been analyzed. Some polymorphic variations in these genes have been associated in some works with significant differences in BMD, with even more significant contributions when associations of different gene polymorphisms were analyzed. Again, the molecular basis for the contribution of these alleles to bone mass determination has not yet been described. A different approach has been attempted by linkage analysis of loci involved in bone density in pedigrees with low BMD using BMD as a quantitative trait. Recent results do not confirm, in these families, any association with any of the previously reported genes, but rather with other as yet unidentified genes. The genetic contribution to mild variations in the general population, as a result of environmental and endogenous individual influences, probably differs completely from that providing a pathologic BMD.
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PMID:Genetic determinants of bone mass. 1046 Oct 16

Immunoreactivities of total apolipoprotein E (ApoE-IR), amyloid beta peptide(1-42) (Abeta42-IR), interleukin-6 (IL-6-IR), substance P (SPIR) and total tau protein (TTIR) were measured in lumbar cerebrospinal fluid samples of patients with Alzheimer's disease (AD), non-Alzheimer's dementias (NAD), neurological disorders without cognitive impairment (OND) and controls without central nervous system disease using sensitive and specific enzyme immunoassay methods. TTIR was highly significantly increased (P < 0,001) and Abeta42-IR was significantly decreased (P < 0,001 vs. OND/CO, P < 0,03 vs. NAD) in the AD cohort compared with the other diagnostic groups. Significant increases in AD were also found for ApoE-IR (P < 0,001) and IL-6 (P < 0,03), but there was a considerable overlap between groups. In the total AD cohort, SPIR was not significantly changed, but AD patients with late disease onset (>65 years) showed significantly higher values than both early onset patients (<65 years) and controls (P < 0,05). Discriminant function analysis showed that Abeta42-IR (cut-off value 375pg/ml) and TTIR (cut-off value 440 pg/ml) levels contributed most to the group classification of patients. At 85% sensitivity for AD and 100% specificity for controls, the combined evaluation of Abeta42-IR and TTIR in this cross-sectional study resulted in a graph separating AD from non-AD patients with increased specificity of 91% and 75% for AD versus OND and NAD, respectively.
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PMID:Clinical significance of neurobiochemical profiles in the lumbar cerebrospinal fluid of Alzheimer's disease patients. 1131 76

Interleukin-6 (IL-6) gene expressed in bone marrow-derived stromal cells and osteoblasts contributes to the state of mineralization and its control by estradiol may be involved in the development of post-menopausal osteoporosis. Since IL-6 is also expressed in the different cell populations of the arterial wall, the purpose of this study was to gain more insight into its involvement in the atherosclerotic process and the atheroprotective effect of estradiol by studying double deficient mice at the apolipoprotein E and IL-6 loci (IL-6(-/-)/E(-/-)). At 1 year of age, IL-6(-/-)/E(-/-) mice showed similar hypercholesterolemia to IL-6(+/+)/E(-/-) mice but presented significantly larger and more calcified lesions. In younger mice (sixteen weeks of age), no significant difference in fatty streaks could be detected in IL-6(+/+)/E(-/-), IL-6(+/-)/E(-/-) and IL-6(-/-)/E(-/-) mice on a normal chow diet. Estrogen supplementation at this age induced a decrease of fatty streak formation in all three genotypes. The combined data indicate that IL-6 expression is involved at the fibrous plaque stage of the atherosclerotic process but does not constitute a direct target for estradiol to prevent fatty streak formation.
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PMID:Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17beta-estradiol in apolipoprotein E-deficient mice. 1139 27

Osteoporosis is a disease affecting mainly women but also an increasing number of men. The destruction of the bone microarchitecture and the reduction of bone mass lead to increased fragility and pathologic bone fractures. Family studies and twin studies have shown that peak bone mass, mechanical strength, and physiological bone turnover are subject to genetic control. Vitamin D receptor polymorphisms were one of the first genetic factors suggested to influence bone phenotype, although their impact on bone metabolism was initially overestimated. Meanwhile, polymorphisms in numerous other genes such as collagen I alpha 1, estrogen receptor, transforming growth factor beta (TGF-beta), interleukin-1, interleukin-6, calcitonin, parathyroid hormone, and apolipoprotein E have been found to be associated with bone mineral density. In the interpretation of genetic findings, genetic differences between different ethnic groups, environmental factors such as calcium intake, vitamin D status, hormonal status, body size, and total body bone mineral density have to be considered. Understanding the molecular physiology of the genes described in this article and all genes influencing bone metabolism identified in the future will enable us to identify persons at risk for osteoporosis and to develop more specific therapies.
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PMID:[Genetics of osteoporosis]. 1151 78

The goal of the present study was to elucidate mechanisms for angiotensin II (Ang II) induction of oxidized low density lipoprotein (Ox-LDL) uptake by macrophages, the hallmark of early atherosclerosis. Compared with placebo treatment, Ang II injections (0.1 mL, 10(-7) mol/L per day) for 2 weeks to apolipoprotein E-deficient mice significantly increased Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). These effects were abolished by treatment with losartan (5 to 50 mg/kg per day) before Ang II administration. Because no such effect was obtained in vitro, the ex vivo effect of Ang II on macrophage uptake of Ox-LDL could be mediated by a factor that is not expressed at a significant level in vitro. Because Ang II stimulates cellular production of interleukin-6 (IL-6), we analyzed the possible role of IL-6 as a mediator of Ang II-mediated cellular uptake of Ox-LDL by using several approaches. First, incubations of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Second, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression compared treatment with Ang II alone. Finally, Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Thus, we conclude that a novel mechanism for Ang II atherogenicity, related to macrophage cholesterol accumulation and foam cell formation, may involve its stimulatory effect on macrophage uptake of Ox-LDL, a process mediated byIL-6.
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PMID:Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6. 1155 73

Coronary heart disease (CHD) is one of the main leading causes of death worldwide. CHD is a complex condition resulting from numerous gene-gene and gene-environment interactions. A large number of candidate genes exist. We review the evidence for the role of apolipoprotein E, lipoprotein lipase and interleukin-6 in CHD and their interaction with smoking (an environmental risk). The main objective of genetic research into CHD is to provide a complete risk assessment, complementing the well-studied traditional clinical and biochemical risk factors. Unravelling the role that functional gene polymorphisms play in determining risk, and in determining the levels of intermediate phenotypes is crucial to our understanding of the key metabolic pathways and physiology not only in the diseased, but also in the disease-free state. The identification of new molecules (implicated in the relevant metabolic pathways) may subsequently lead to potential targets for therapeutic intervention. Improving our molecular understanding may also lead to the development of improved diagnostics. Sequencing of the entire genome is now a reality. Advances in technology, such as the development of "gene chips" may allow us to study 100 000 genes at a time on a single chip. Such advances will amplify the power available to us in the realms of research into genetic physiology and interaction with environmental stimuli. The insights that these novel approaches may yield are eagerly awaited.
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PMID:The molecular genetics of cardiovascular disease: clinical implications. 1254 51


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