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)

Both chlamydial and human heat shock protein 60s (HSP 60), which colocalize in human atheroma, may contribute to inflammation during atherogenesis. We tested the hypothesis that chlamydial or human HSP 60 activates human endothelial cells (ECs), smooth muscle cells (SMCs), and monocyte-derived macrophages. We examined the expression of adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), and the production of the proinflammatory cytokine interleukin-6 (IL-6). We also tested whether either HSP 60 induces nuclear factor-kappaB (NF-kappaB), which contributes to the gene expression of these molecules. Either chlamydial or human HSP 60 induced E-selectin, ICAM-1, and VCAM-1 expression on ECs similar to levels induced by Escherichia coli lipopolysaccharide (LPS). Each HSP 60 also significantly induced IL-6 production by ECs, SMCs, and macrophages to an extent similar to that induced by E. coli LPS, as assessed by enzyme-linked immunosorbent assay (ELISA). In ECs, either HSP 60 triggered activation of NF-kappaB complexes containing p65 and p50 Rel proteins. Heat treatment abolished all these effects, but did not alter the ability of E. coli LPS to induce these functions. Chlamydial and human HSP 60s therefore activate human vascular cell functions relevant to atherogenesis and lesional complications. These findings help to elucidate the mechanisms by which a chronic asymptomatic chlamydial infection might contribute to the pathophysiology of atheroma.
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PMID:Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. 1002 66

Bone marrow (BM) environment is thought to support the growth of myeloma cells and thus to play an important role in the pathogenesis of multiple myeloma (MM). Because interleukin-6 (IL-6) is an essential growth factor in MM, we have examined the effects of two myeloma cell lines (U266 and ARH-77) on the IL-6 production by BM stromal cells in a co-culture system. These cell lines strongly stimulate the IL-6 production and IL-6 triggering was partially dependent on physical contact between lines and stroma. The percentages of cell adhesion to stromal layers were 39% and 25% respectively for ARH77 and U266 cell lines. Inhibition studies with blocking monoclonal antibodies showed the importance of CD49d/CD106 and CD11a/CD54 interactions in the stimulation of IL-6 production by stromal cells. However, cell-to-cell contact was not an absolute requirement for IL-6 production. Cytokines, of which TNF-alpha and IL-1beta produced by MM or accessory cells, were also able to stimulate IL-6 production by fibroblasts and show additive effects. In adhesion assays, TNF-alpha and IL-1beta were able to increase the adhesion of MM cells to stromal cells. CD54 was upregulated by IL-1beta, TNF-alpha or a contact with MM cells while CD106 expression was not, suggesting only a functional change of this molecule. However, the role of monoclonal antibodies, directed against these factors, confirmed the role of TNF-alpha in the IL-6 production by stromal cells, while any IL-1beta intervention was not shown in our co-culture system. IL-6 favoured and maintained adhesion of MM cells to stromal cells spontaneously since its reintroduction in the favoured co-culture system restored their decreased adhesion observed on a glutaraldehyde fixed stromal layer. Overall our data suggest a functional overlap between cytokines and adhesion molecules for the paracrine IL-6 production.
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PMID:Interdependence between cytokines and cell adhesion molecules to induce interleukin-6 production by stromal cells in myeloma. 1003 6

Leukocyte infiltration of cerebral vessels in cocaine-associated vasculopathy suggests that cocaine may enhance leukocyte migration. We have investigated cocaine's effects on leukocyte adhesion in human brain microvascular endothelial cell (BMVEC) cultures and monocyte migration in an in vitro blood-brain barrier (BBB) model constructed with BMVEC and astrocytes. Cocaine (10(-5) to 10(-9) M) enhanced adhesion of monocytes and neutrophils to BMVEC. In the BBB model, cocaine (10(-4) to 10(-8) M) enhanced monocyte transmigration. Cocaine increased expression of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1, CD54), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1) on BMVEC. The peak effect on ICAM-1 expression was between 6 and 18 h after treatment. ICAM-1 was increased by cocaine in BMVEC, but not in human umbilical vein endothelial cells, and the enhancement was greater in a coculture of BMVEC with monocytes. ICAM-1 expression was enhanced by a transcriptional mechanism. Polymyxin B inhibited up-regulation of adhesion molecules by LPS but not by cocaine. In LPS-activated BMVEC/monocyte coculture, cocaine increased secretion of tumor necrosis factor-alpha and interleukin-6. Taken together, these findings indicate that cocaine enhances leukocyte migration across the cerebral vessel wall, in particular under inflammatory conditions, but the effects are variable in different individuals. Cocaine's effects are exerted through a cascade of augmented expression of inflammatory cytokines and endothelial adhesion molecules. These could underlie the cerebrovascular complications of cocaine abuse.
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PMID:Cocaine enhances brain endothelial adhesion molecules and leukocyte migration. 1021 56

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

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.
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PMID:Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria. 1043 50

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. PPAR have profound effects on the metabolism of lipoproteins and fatty acids. PPAR alpha binds hypolipidemic fibrates, whereas PPAR gamma has a high affinity for antidiabetic glitazones. Both PPAR are activated by fatty acids and their derivatives. Activation of PPAR alpha increases the catabolism of fatty acids at several levels. In the liver, it increases uptake of fatty acids and activates their beta-oxidation. The effects that PPAR alpha exerts on triglyceride-rich lipoproteins is due to their stimulation of lipoprotein lipase and repression of apolipoprotein CIII expression, while the effects on high-density lipoproteins depend upon the regulation of apolipoproteins AI and AII. PPAR gamma has profound effects on the differentiation and function of adipose tissue, where it is highly expressed. PPAR are also expressed in atherosclerotic lesions. PPAR are present in vascular endothelial cells, smooth muscle cells, monocytes, and monocyte-derived macrophages. Via negative regulation of nuclear factor-kappa B and activator protein-1 signalling pathways, PPAR alpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, and endothelin-1. Furthermore, PPAR alpha inhibits expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1 and induces apoptosis in monocyte-derived macrophages. PPAR gamma activation in macrophages and foam cells inhibits the expression of activated genes such as inducible nitric oxide synthase, matrix metalloproteinase-9 and scavenger receptor A. PPAR gamma may also affect the recruitment of monocytes in atherosclerotic lesions as it is involved in the expression of VCAM-1 and intracellular adhesion molecule-1 in vascular endothelial cells. The involvement of PPAR in atherosclerosis, a disease with a chronic inflammatory character, suggests that they may play a role in other inflammatory-related diseases as well.
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PMID:Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. 1100 63

Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that a variable number tandem repeat (vntr) polymorphism in the 3'flanking region of the IL-6 gene (C allele) is associated with altered activity of IL-6 in vivo. Therefore, we analyzed the frequency distribution of IL-6 gene C allele vntr poymorphism in 96 MS patients and 106 ethnically matched healthy controls. Moreover, possible correlations between genotypic differences of IL-6 gene and serum levels of IL-6, soluble IL-6 receptor (sIL6-R), soluble gp130 (sgp130), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were investigated. There were no differences in the allelic distribution of the IL-6 gene C allele between MS patients and healthy controls, and no association of the IL-6 gene C allele with serum levels of IL-6, sIL-6R, spg130, sICAM and sVCAM-1 was found.
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PMID:No association of serum levels of interleukin-6 and its soluble receptor components with a genetic variation in the 3'flanking region of the interleukin-6 gene in patients with multiple sclerosis. 1107 34

Endothelial cells respond to double-stranded RNA (dsRNA) with expression of a number of important immunomodulatory and inflammatory response genes, including adhesion molecules, cytokines, and antiviral genes. Considerable differences are seen when genes are induced by dsRNA compared with cytokines. Much higher levels of mRNA for interleukin-6 (IL-6), 2',5'-oligoadenylate synthetase (2',5'-OAS), protein kinase (PKR), and interferon (IFN) regulatory factor-1 (IRF-1) result from incubation with dsRNA than with IL-1beta, tumor necrosis factor-alpha (TNF-alpha), or IFN-alpha, whereas the differences in vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA expression in response to dsRNA, IL-1beta, and TNF-alpha are relatively minor. IFN-alpha priming enhances responsiveness of some, but not all, genes to dsRNA but not to IL-1beta, but the optimal time for pretreatment varies considerably among different dsRNA-responsive genes. Protein translation is reduced in human umbilical vein endothelial cells (HUVEC) in response to incubation with dsRNA, and this decrease is accentuated if cells are primed with IFN-alpha. Despite this decrease, IFN-alpha priming causes very high levels of IL-6 protein expression in response to dsRNA but not in response to IL-1beta or TNF-alpha. These studies demonstrate that priming with class I IFN can enhance the response to dsRNA through the heightened expression of genes that contribute to both the cellular response to viral infection and the host immunologic response.
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PMID:Modulation of double-stranded RNA-mediated gene induction by interferon in human umbilical vein endothelial cells. 1109 58

The aim of this study was to evaluate the diagnostic capacity of a number of blood components such as soluble adhesion molecules, interleukin-6 (IL-6), myeloperoxidase (MPO) and lysozyme in the distinction of acute bacterial and viral infections. Blood was taken from 115 acutely infected patients at admission before any treatment and in some cases on several consecutive days. 35 of the patients had a definite viral cause for their infection and 66 a bacterial cause. All variables were raised in patients with acute bacterial infections. Soluble vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin, lysozyme and MPO were also raised in acute viral infections, but for sE-selectin and MPO less so than in bacterial infections. Evaluation of the diagnostic power showed that for MPO and IL-6 at cut-offs of 1300 microg/l and 100 ng/l, respectively, the positive predictive value was 97% and 100% and the negative predictive value 78% and 76%, respectively, in the classification of acute bacterial infections. In the distinction between viral or bacterial causes of acute infections in otherwise healthy subjects serum measurements of MPO and IL-6 are valuable tools and should be considered as diagnostic aids in the routine setting. The soluble adhesion molecules did not offer any further information in this respect.
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PMID:Soluble adhesion molecules, cytokines and cellular markers in serum in patients with acute infections. 1134 22

Normal human bone marrow stroma cells include stem cells for both haemopoietic and osteochondrogenic lineages and express both bone morphogenetic protein (BMP) type I and type II receptors. As a member of the TGF-beta super-family, BMP-6 binds to both BMP type I and type II receptors and is involved in the developmental processes of renal and hepatic systems as well as of human foetal intestine. Also, BMP-6 induces osteoblastic differentiation of pluripotent mesenchymal cells and is an autocrine stimulator of chondrocyte differentiation. The present study was carried out to investigate the effect of BMP-6 on human cobblestone-area-forming cells (CAFC), that represent the functional primitive repopulating haemopoietic stem cell in long-term bone marrow culture. Also, the effect of BMP-6 on marrow stroma production of interleukin-6, -11 and their common receptor gp130 that is expressed in haemopoietic stem cells and is indispensable for their proliferation and tri-lineage differentiation was examined. Moreover, the effect of BMP-6 on marrow stroma release of soluble adhesion molecule VCAM-1 mediating the primitive haemopoietic stem cell adhesion to marrow stroma was examined. The number of CAFC was significantly reduced after BMP-6 treatment from 88+/-10 per 10(5)cells in control cultures in a dose dependent manner to only 48+/-3 per 10(5)cells in 50 ng/ml BMP-6-treated cultures, P< 0.01. Quantitative ELISA measurement revealed 50 ng/ml BMP-6 was able to significantly reduce IL-6 and IL-11 production from marrow stroma, P< 0.01. Also, BMP-6 significantly increased soluble gp130 release by 7.4-fold in 50 ng/ml BMP-6-treated marrow stroma cultures. The profound rapid increase in this natural antagonist of human IL-6 cytokine family may reduce the gp130 signaling. Also, the soluble VCAM-1 released increased by two-fold in 50 ng/ml BMP-6-treated marrow stroma cultures. The marked increase in the soluble form may exert an antagonist effect on the function of VCAM-1 (ligand for VLA4). Recently, blocking the VLA4/VCAM-1 adhesion pathway was shown to mobilise haemopoietic CD34 positive cells in normal individuals. Also, we previously observed a significantly lower expression of VLA4 (CD49d) on G-CSF-mobilised blood CD34 positive cells than on bone marrow CD34 positive cells before mobilisation in the same normal donors. Since BMP are currently being used in clinical trials for bone repair and fracture healing, the present results suggest a possible role for BMP-6 in mobilising CD34 positive cells for transplantation. Further in vitro tests are required to evaluate this potential mobilising role of BMP-6 in human long-term bone marrow culture.
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PMID:Effect of bone morphogenetic protein-6 on haemopoietic stem cells and cytokine production in normal human bone marrow stroma. 1140 30


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