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)

Intercellular adhesion molecule-3 (ICAM-3, CD50), an adhesion receptor of the immunoglobulin superfamily, is suggested to play a key role in adhesive cellular interactions during the initial phase of an immune response. We here provide evidence that ICAM-3 is abundantly expressed by cells of the human mast cell line HMC-1 and, to a lower degree, by purified skin mast cells, as demonstrated by flow-cytometry, ELISA and RT-PCR. ICAM-3 immunoprecipitated from surface biotinylated HMC-1 cells migrates as a broad band of Mr 124,000 by Western blot analysis. We also demonstrate that monoclonal antibodies directed against ICAM-3 are capable of inducing rapid HMC-1 cell aggregation, the extent of which strongly depends on the epitope recognized by the mAb applied. Interestingly, although inhibitable by two of six mAbs against LFA-1, HMC-1 aggregation induced via ICAM-3 appears to be mediated by an adhesive pathway independent of LFA-1. Dermal mast cells are also aggregated with anti-ICAM-3 mAbs, a phenomenon which has not been described before for isolated tissue mast cells. However, this process displays slower kinetics, as compared to HMC-1 cells. That anti-ICAM-3 mAbs are able to mediate biological effects is further illustrated by their capability to increase stimulation-dependent release of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8 from HMC-1 cells. Taken together, these results indicate that ICAM-3 is not only expressed by immature and mature human mast cells, but also possesses functional relevance and may therefore play a significant role in mast cell associated processes.
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PMID:ICAM-3 (CD50) is expressed by human mast cells: induction of homotypic mast cell aggregation via ICAM-3. 1062 4

Phosphorothioate oligodeoxynucleotides produce splenomegaly and mononuclear cell infiltrates in multiple organs in mice after repeated i.v. administration. Several phosphorothioate oligodeoxynucleotides were studied to better understand the basis of immunostimulatory properties of these molecules in mice and to study the effects of chemically modified oligonucleotides. Chemical modifications examined included 5-methyl cytosine and 2'-methoxyethoxy substituents. Male mice (six per group) were treated with oligonucleotide concentrations of 0, 2, 10, or 50 mg/kg by i.v. injection every other day for 14 days. Immune stimulation was assessed 24 h after the last dose by measuring spleen weight, or histologic and immunohistochemical examination of liver and kidney. Immune stimulation was dose-dependent for the phosphorothioate oligodeoxynucleotides studied, but potency varied as a function of sequence. Results from this study reveal that there is a close correlation between the extent of splenomegaly and other evidence of immune stimulation, such as the severity of cell infiltrates in liver and kidney in mice. Immunohistochemical analysis indicated that cell infiltrates in liver and kidney were primarily mononuclear cells associated with increased expression of the endothelial-leukocyte cellular adhesion molecule intracellular adhesion molecule-1 and the cytokine interleukin-6. Immune stimulation was markedly decreased with oligonucleotides containing the 5-methyl cytosine and further decreased by 2'-methoxyethoxy modifications. Administration of these modified oligonucleotides to mice did not produce splenomegaly even at the 50-mg/kg dose, and only produced minimal cell infiltrates despite the presence of comparable or greater tissue oligonucleotide concentrations. Thus, chemical modifications appeared to increase the tolerability profile for these compounds that are representative of the second generation of antisense oligonucleotides.
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PMID:Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. 1064 Feb 82

Leukocyte infiltration and adhesion molecule activation play a central role in the pathogenesis of angiotensin II (Ang II)-induced end-organ damage in double transgenic rats (dTGR) harboring human renin and angiotensinogen genes. We tested the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects against the Ang II-induced myocardial and renal damage in dTGR. Furthermore, we investigated the influence of CsA on interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expression and the DNA binding activity of transcription factor necrosis factor-kappaB (NF-kappaB). The 4-week-old rats were divided into 4 groups: (1) control dTGR (n=20), (2) dTGR plus CsA (5 mg/kg SC for 3 weeks, n=15), (3) normotensive Sprague-Dawley (SD) rats (n=10), and (4) SD rats plus CsA (n=8). In dTGR, CsA completely prevented cardiovascular death (0 of 15 versus 9 of 20), decreased 24-hour albuminuria by 90% and systolic blood pressure by 35 mm Hg, and protected against the development of cardiac hypertrophy. Whole blood CsA concentrations 24 hours after the last drug treatment were 850+/-15 ng/mL. Semiquantitative ED-1 and Ki-67 (a nuclear cell proliferation-associated antigen) scoring showed that CsA prevented perivascular monocyte/macrophage infiltration and prevented cell proliferation in the kidneys and hearts of dTGR, respectively. The beneficial effects of CsA were, at least in part, mediated by the suppression of IL-6 and iNOS expression. Electrophoretic mobility shift assay revealed that CsA regulated inflammatory response in part through the NF-kappaB transcriptional pathway. In contrast to dTGR, CsA increased blood pressure in normotensive SD rats by 10 mm Hg and had no effect on cardiac mass or 24-hour urinary albumin excretion. Perivascular monocyte/macrophage infiltration, IL-6, and iNOS expression or cell proliferation were not affected by CsA in SD rats. Our findings indicate that CsA protects against Ang II-induced end-organ damage and underscore the central role of vascular inflammatory response in the pathogenesis of myocardial and renal damage in dTGR. The beneficial effects of CsA in the kidney and heart are mediated, at least in part, by suppression of IL-6 and iNOS expression via NF-kappaB transcriptional pathway.
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PMID:Cyclosporin A protects against angiotensin II-induced end-organ damage in double transgenic rats harboring human renin and angiotensinogen genes. 1064 25

Recombinant adenovirus (rAd) infection is one of the most effective and frequently employed methods to transduce dendritic cells (DC). Contradictory results have been reported recently concerning the influence of rAd on the differentiation and activation of DC. In this report, we show that, as a result of rAd infection, mouse bone marrow-derived immature DC upregulate expression of major histocompatibility complex class I and II antigens, costimulatory molecules (CD40, CD80, and CD86), and the adhesion molecule CD54 (ICAM-1). rAd-transduced DC exhibited increased allostimulatory capacity and levels of interleukin-6 (IL-6), IL-12p40, IL-15, gamma interferon, and tumor necrosis factor alpha mRNAs, without effects on other immunoregulatory cytokine transcripts such as IL-10 or IL-12p35. These effects were not related to specific transgenic sequences or to rAd genome transcription. The rAd effect correlated with a rapid increase (1 h) in the NF-kappaB-DNA binding activity detected by electrophoretic mobility shift assays. rAd-induced DC maturation was blocked by the proteasome inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) or by infection with rAd-IkappaB, an rAd-encoding the dominant-negative form of IkappaB. In vivo studies showed that after intravenous administration, rAds were rapidly entrapped in the spleen by marginal zone DC that mobilized to T-cell areas, a phenomenon suggesting that rAd also induced DC differentiation in vivo. These findings may explain the immunogenicity of rAd and the difficulties in inducing long-term antigen-specific T-cell hyporesponsiveness with rAd-transduced DC.
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PMID:Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-dependent pathway. 1100 Feb 34

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

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-mediated lowering of serum cholesterol has been associated with a significant reduction in cardiovascular morbidity and mortality. Recent studies suggest that additional non-lipid lowering effects (eg, endothelial stabilization, anti-inflammatory, antithrombogenic) may be important in modulating their effectiveness. Dyslipidemia is common in end-stage renal disease (ESRD), and hemodialysis patients have increased cardiovascular morbidity and mortality. Cerivastatin, a new statin with powerful low-density lipoprotein-cholesterol (LDL-C) lowering capabilities, possesses some unique non-LDL-C-mediated properties that may contribute to a reduction of coronary events in the patient with ESRD. The primary objective of this multicenter multinational study of 1,054 hemodialysis patients is to compare 2 years of treatment with cerivastatin (0.4 mg/d) versus placebo on the composite clinical event rate of myocardial infarction, sudden cardiac death, ischemic stroke, and the need for coronary arterial bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) procedures in these patients. Changes in lipids, inflammatory proteins including heat stable C-reactive protein (hsCRP), interleukin-6 (IL-6), oncostatin-M, intracellular adhesion molecule-1 (ICAM-1) and monocyte-chemoattractant protein-1 (MCP-1), as well as markers of cardiac muscle pathology, such as troponin I and troponin T, will be assessed in a subset of patients. This study is the first of its kind to assess the effect of a statin on the reduction of cardiovascular morbidity and mortality in an incident hemodialysis population. It will determine whether treatment with cerivastatin can effectively reduce the significant cardiovascular morbidity and mortality.
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PMID:The CHORUS (Cerivastatin in Heart Outcomes in Renal Disease: Understanding Survival) protocol: a double-blind, placebo-controlled trial in patients with esrd. 1115 61

This study aimed to evaluate the possibility to detect early changes in gut-associated lymphoid tissue related to an inflammatory response. Anaesthetised pigs were subjected to faecal peritonitis (n = 9) or to a sham procedure (n = 8). Blood from the vena cava and the superior mesenteric vein was repeatedly sampled, and the levels of interleukin-6 (IL-6) were analysed. Biopsies of the small intestine and mesenteric lymph nodes (MLNs), harvested at 300 min, were incubated with monoclonal antibodies specific for CD2 (T lymphocytes), IgM (B lymphocytes) and CD11a/CD18 (leucocyte adhesion molecule). The number of positive (+) cells was scored. During peritonitis, IL-6 increased significantly. Compared to controls, the number of CD2+ cells decreased, IgM+ cells tended to increase and CD11a/CD18+ cells increased in the mucosa during peritonitis. In MLNs, the number of cells positive for all studied markers increased during peritonitis. We conclude that peritonitis causes an inflammatory response in the gut reflected by changes in the distribution of immune cells in gut-associated lymphoid tissue and release of IL-6 to venous blood.
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PMID:Immune cell distribution in gut-associated lymphoid tissue and synthesis of IL-6 in experimental porcine peritonitis. 1118 15

The changes in serum concentrations of cytokines such as interleukin-1 (IL-1) beta, interleukin-6 (IL-6), tumor necrosis factor (TNF) alpha and a soluble-intercellular adhesion molecule (sICAM-1) has been investigated in patients with stable angina and acute myocardial infarction. Thirty-four patients with stable angina (SA), 15 with acute myocardial infarction (AMI), and 20 subjects in the control (C) group were included in the study. The mean serum concentrations of sICAM-1, IL-1-beta, IL-6, and TNF-alpha differed significantly among the three groups. Serum concentrations of IL-1 beta, sICAM-1, and TNF-alpha were comparable in the AMI and SA groups and higher than those found in the C group (p < 0.001). The serum concentration of IL-6 was more than twice as high in the AMI group as compared to the other two groups (p < 0.001). The mean serum concentrations of IL-1 beta, TNF-alpha, and IL-6 were comparable in the AMI and SA groups and higher than in the C group.
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PMID:Circulating interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and soluble ICAM-1 in patients with chronic stable angina and myocardial infarction. 1122 83

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

Interleukin-6 (IL-6) binds to human gingival fibroblasts (HGF) in the presence of a soluble form of IL-6 receptor (sIL-6R). We investigated the effects of IL-6 on the functions of HGF in the presence of sIL-6R. HGF changed their morphology from spindle-shaped to round, and detached from the culture dish by stimulation with IL-6/sIL-6R. In this condition, a signal transducer gp130 and a transcription factor Stat3 were phosphorylated, resulting in activation of transcription factors Stat3 and C/EBPbeta. Cytoskeletal beta-actin and adhesion molecule integrin-alpha5, a subunit of alpha5beta1 integrin (VLA-5), were found to possess potential binding domains for these transcription factors in their promoters. Accumulation of beta-actin and integrin-alpha5 mRNA decreased, contrary to the expectation of the induction of gene transcription. Furthermore, the decrease in their mRNAs was associated with reduced expression of both actin and VLA-5 proteins. These results suggest that the expression of VLA-5 and actin was down-regulated in HGF through an IL-6 signaling pathway, resulting in impairment of HGF adherence.
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PMID:Impairment of gingival fibroblast adherence by IL-6/sIL-6R. 1143 12


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