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)

Tea has been shown to possess several health beneficial properties primarily due to its polyphenolic content. The major polyphenolic compounds in black tea leaves are theaflavins (TFs) formed by oxidative coupling of catechins in tea leaves during its processing. In this paper, we report the characterization of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear inflammatory model and the inhibitory effects of major black tea TFs derivatives on this inflammation. In addition, the effect on inflammatory biomarkers, such as proinflammatory cytokines and arachidonic acid metabolites, are reported as well. A single topical application of TPA to ears of CD-1 mice induced a time- and dose-dependent increase in edema as well as formation of proinflammatory cytokine proteins interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in mouse ears. A single topical application of equimolar of black tea constituents (TF, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate) strongly inhibited TPA-induced edema of mouse ears. Application of TFs mixture to mouse ears 20 min prior to each TPA application once a day for 4 days inhibited TPA-induced persistent inflammation, as well as TPA-induced increase in IL-1beta and IL-6 protein levels. TFs also inhibited arachidonic acid (AA) metabolism via both cyclooxygenase (COX) and lipoxygenase pathways. This observation was substantiated by decreased amounts of AA metabolites prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels. Combined application of TF and sulindac, a nonsteroidal anti-inflammatory drug resulted a significant synergetic anti-inflammatory effect. Oral administration of TFs or the hot water extract of black tea leaves also significantly inhibited TPA-induced edema in mouse ears. In conclusion, proinflammatory cytokines, IL-1beta and IL-6, as well as the intermediated metabolites of AA, PGE2, and LTB4 are good biomarkers for inflammation. Black tea constituents, TF and its derivatives, had strongly anti-inflammatory activity in vivo which may be due to their ability to inhibit AA metabolism via lipoxygenase and COX pathways.
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PMID:Inhibitory effects of black tea theaflavin derivatives on 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and arachidonic acid metabolism in mouse ears. 1640 5

This study evaluates the antipyretic activity of nimesulide, a cyclooxygenase (COX-2) selective inhibitor in rats. The effects of nimesulide on lipopolysaccharide (LPS)-induced cerebrospinal prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) and on plasma tumor necrosis factor-alpha (TNF-alpha) levels were also evaluated. Male Wistar rats received an i.p. injection of LPS, or i.c.v. injections of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), TNF-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha), arachidonic acid, PGE(2), PGF(2alpha), corticotrophin-releasing factor (CRF) or endothelin-1 (ET-1). Nimesulide or indomethacin administered i.p 30 min prior LPS, IL-1beta, IL-6, TNF-alpha or arachidonic acid reduced the febrile response and PGE(2) or PGF(2alpha) levels in LPS-febrile rats but did not modify PGE(2)-induced fever. Nimesulide, but not indomethacin, reduced the fever induced by MIP-1alpha, PGF(2alpha), CRF or ET-1. Plasma TNF-alpha levels in LPS-treated rats were also reduced by nimesulide. These findings confirm that the antipyretic effect of nimesulide differs from the antipyretic scenario with the non-selective cyclooxygenase blocker indomethacin. Additional mechanisms, including inhibition of increased plasma TNF-alpha, may contribute to its antipyretic activity in rats.
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PMID:Nimesulide-induced antipyresis in rats involves both cyclooxygenase-dependent and independent mechanisms. 1681 79

Aspirin and other cyclooxygenase inhibitors can increase levels of tumor necrosis factor-alpha and engage pro-apoptosis paths and/or anti-apoptosis paths. Seemingly conflicting data are briefly reviewed. Aspirin has been shown to slightly increase survival duration in multiple myeloma. In this brief note caution is raised about use of aspirin and COX inhibitors generally in inflammatory states and specifically in myeloma. Should they increase tumor necrosis factor-alpha they could exacerbate disease. A figure is presented showing the tendency for interleukin-6 and tumor necrosis factor-alpha, both demonstrated to be growth factors in myeloma, to be counter-regulated. Since both are now easily measured by specialty labs, it would be reasonable to monitor these during myeloma treatment generally, and particularly when using aspirin, COX inhibitors, or any other drug with potential to increase these growth factors.
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PMID:Aspirin, TNF-alpha, NFkB, and survival in multiple myeloma: the importance of measuring TNF-alpha. 1713 47

Epidemiological and experimental data implicate maternal-fetal infection and an associated increase in circulating cytokines in the etiology of cerebral palsy. We have previously shown that pretreatment of newborn mice with systemic interleukin-1-beta exacerbates ibotenate-induced excitotoxic brain lesions. Such lesions are consistent with those observed in cerebral palsy. The present study builds on this murine model to assess the role of cyclooxygenase in interleukin-1-beta-induced brain toxicity. Pups pretreated with interleukin-1-beta developed greater ibotenate-induced brain damage than controls, an effect blocked by the co-administration of nimesulide (cyclooxygenase-2 inhibitor) or indomethacin (cyclooxygenase-1 and -2 inhibitor). Cyclooxygenase inhibitor administration prevented the interleukin-1-beta-induced increase in the production of brain prostaglandin E(2) (a cyclooxygenase metabolite) and changes in the expression of brain interleukin-6, interleukin-18, tumor necrosis factor-alpha, and brain-derived neurotrophic factor. It also stimulated the expression of brain interleukin-10. Our data suggest that the sensitizing effects of circulating inflammatory cytokines on the brain are mediated by the inducible isoform cyclooxygenase-2, which generates excess prostaglandin E(2). Some of these deleterious effects could involve an autocrine/paracrine loop leading to a disruption of the balance between pro- and anti-inflammatory cytokines in the brain.
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PMID:Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice. 1716 28

Sickness behaviour (SB) consists of the set of adaptive responses of the host to severe infections and inflammation. It includes, among others, the thermoregulatory responses such as regulated increase (fever) and/or decrease (anapyrexia) of body temperature (T(b)), decrease of motor activity (lethargy), and loss of appetite (hypophagia) resulting in a transient loss of body weight. It is thought that SB is partially induced by the immune-derived mediators such as cytokines and prostaglandins acting on the central nervous system. It has repeatedly been shown, on the other hand, that severe infections (pneumonia, tissue septicemia) can impair processes of the gases exchange both in the lungs and in distal tissues including brain, which may lead to hypoxia of the affected organs. Therefore, we have tested the hypothesis that hypoxia may also provoke SB. The study was conducted on freely moving biotelemetered mice kept at 28 degrees C ambient and 12/12 h light/dark cycle. We demonstrate that mice exposed for 7 days to hypoxia (11%O(2)) displayed all symptoms of SB. Interleukin-6 deficient mice (IL-6 KO) revealed reduced SB symptoms under hypoxic conditions. Recovery of the hypoxia-exposed mice to a normal rhythm in T(b), motor activity and feeding was unaffected by mepacrine, a phospholipase A(2) blocker. The recovery, however, was significantly impaired by indomethacin, a cyclooxygenase inhibitor. Exposure to hypoxemia resulted in significant elevation of plasma IL-6 in both untreated and treated with lipopolysaccharide (LPS) mice. It inhibited, however, a generation of blood prostaglandins (PGE(2)) in mice. Based on these data we conclude that IL-6 and accumulation of free arachidonic acid in biomembranes contribute to hypoxemia- induced SB.
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PMID:Hypoxia-induced sickness behaviour. 1724 71

We studied the influence of the inhibitory effect of clarithromycin (CAM) and erythromycin (EM) on the production of macrophage inflammatory protein (MIP)-2, interleukin-6 (IL-6), and prostaglandin E(2) (PGE(2)), as well as PGE(2) receptor (EP(2)) expression, by LPS-stimulated RAW264.7 cells. Production of IL-6 was significantly decreased by treatment with CAM or EM in a dose-dependent manner, but the inhibitory effect of CAM was significantly weaker than that of EM. In contrast, the production of MIP-2 and PGE(2) was inhibited to the same extent by CAM and EM. LPS induced the expression of EP(2) mRNA and its expression was promoted further by treatment with CAM or EM. In particular, CAM significantly upregulated EP(2) mRNA expression compared with that after stimulation by LPS alone. After treatment with a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), or an EP(2)/EP(4) receptor antagonist (AH6809), the inhibitory effect of CAM and EM on LPS-induced IL-6 production was equalized. These results indicate that macrolide antibiotics upregulate the expression of EP(2), which then attenuates the suppressive effect on IL-6 production of these antibiotics, suggesting that these drugs have a variable anti-inflammatory effect that could influence host defenses.
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PMID:Macrolide antibiotics promote the LPS-induced upregulation of prostaglandin E receptor EP2 and thus attenuate macrolide suppression of IL-6 production. 1732 65

Melanoma progression is often associated with supranormal levels of interleukin-6 (IL-6). Il-6 is an important growth factor for many cases of melanoma. A recent case report by Lejeune et al. [Melanoma Res 2006;16:263-265] of remission of an advanced melanoma during treatment with the cyclooxygenase, (COX) inhibitor rofecoxib can be explained by rofcoxib-mediated lowering of tumor-produced Il-6. Several examples of rofecoxib's ability to lower Il-6 in humans have been published recently in other settings, and many reports indicate that other commonly used COX inhibitors like aspirin, diclofenac, etodolac, indomethacin, naproxen, and many others, also lower Il-6 in humans. These studies are reviewed. The likely mechanism of COX inhibition leading to Il-6 lowering is due to the tendency for Il-6 levels to be controlled by intracellular cyclic adenosine monophosphate (cAMP). Adenylate cyclase is the rate-limiting enzyme in cAMP synthesis. Because adenylate cyclase activity is allosterically enhanced when it binds prostaglandin E, the latter increases Il-6. COX inhibition lowers prostaglandin E levels. This lowers intracellular cAMP levels. Lower cAMP results in lower Il-6 synthesis, lower levels of a required growth factor. Controlled studies are needed to define the role of COX inhibitors in melanoma treatment.
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PMID:Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications. 1767 6

Chicken thrombocytes are equivalent in hemostatic function to mammalian platelets. Platelets are enucleated components of mammalian blood, while thrombocytes are nucleated blood leukocytes of chickens. Platelets and thrombocytes share characteristics that contribute to innate immunity. Experiments were conducted to determine if thrombocytes could respond in vitro to lipopolysaccharide (LPS) of Salmonella minnesota through Toll-like receptor-4 (TLR4). The aim was to activate the signal pathways leading to expression of interleukin-6 (IL-6) and inducible cyclooxygenase (COX-2) and to production of prostaglandin E2 (PGE2). Chicken thrombocytes were found to express TLR4, and LPS-induced an increase in thrombocyte mRNA expression of IL-6 and COX-2 with release of PGE2 into culture media. An increase of COX-2 and PGE2 due to LPS stimulation was inhibited by MEK1 inhibitor PD98059, but IL-6 expression was unaffected by PD98059. The IKK-2 inhibitor BMS345541 inhibited IL-6 and COX-2 with reduction of PGE2 concentrations. Therefore, the MAP kinase (MAPK) pathway activates expression of COX-2 and ultimately PGE2 production, but this pathway has little or no influence on IL-6 expression in thrombocytes. The NF-kappaB pathway also influences COX-2 expression and PGE2 production, and it is a primary activation signaling cascade for IL-6 gene expression in chicken thrombocytes. Thrombocytes represent a major component of the innate immune system of chickens in response to LPS and possibly other microbial products.
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PMID:Thrombocytes respond to lipopolysaccharide through Toll-like receptor-4, and MAP kinase and NF-kappaB pathways leading to expression of interleukin-6 and cyclooxygenase-2 with production of prostaglandin E2. 1782 13

Current thinking supports the notion that several inflammatory proteins intervene with endothelium and haemostatic factors leading to plaque formation and rupture. Of these, C-reactive protein (CRP), monocyte/macrophage colony-stimulating factor (MCSF) and interleukin-6 (IL-6) promote atherogenesis by inducing monocyte-macrophage activation, foam cell formation, platelet activation, tissue factor expression, release of other procoagulant cytokines or downregulation of atheroprotective cytokines such as interleukin 10 and transforming growth factor b-1 (TGFb-1). CRP, MSCF and IL-6 are interrelated and have been found in increased blood concentrations in CAD. Increased levels of CRP and IL-6 predict a higher cardiovascular event rate in the general population and in addition to high MCSF or low TGFb-1 predict adverse outcome in CAD patients independently of traditional risk factors. Moreover, in CAD patients, the predictive value of MCSF is additive and beyond that of CRP suggesting the need of a "multimarker approach" in assessing cardiovascular risk. Accumulating evidence supports the utility of non-invasive markers of subclinical atherosclerosis, namely carotid intimal media thickness, flow mediated dilatation of the brachial artery, augmentation index or pulse wave velocity, in the prediction of cardiovascular risk particularly in primary prevention settings. The combination of these non-invasive tests has been shown to improve their prognostic accuracy compared to each other alone. Although several therapeutic strategies like vaccination against antigens promoting atherogenesis, cyclooxygenase inhibitors, statins, and ACE inhibitors may reduce the levels of these inflammatory markers and improve the non-invasive markers of subclinical atherosclerosis, the impact on cardiovascular risk resulting from these changes is unknown. The combination of an established inflammatory marker such as CRP or a vascular marker such as IMT with novel biochemical and vascular markers of cardiovascular disease may offer additive prognostic information for adverse outcome.
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PMID:Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease. 1837 39

Thrombin exerts multiple effects upon osteoblasts including stimulating proliferation, and inhibiting osteoblast differentiation and apoptosis. Some of these effects are believed to be mediated by the synthesis and secretion of autocrine factors such as growth factors and cytokines. Many but not all cellular responses to thrombin are mediated by members of the protease-activated receptor (PAR) family of G protein-coupled receptors. The current study was undertaken to investigate the nature of thrombin's induction of autocrine factors by analysing the expression of twelve candidate genes in thrombin-stimulated primary mouse osteoblasts. Analysis by quantitative reverse transcription polymerase chain reaction (qRT-PCR) demonstrated that thrombin induced transforming growth factor beta, cyclooxygenase-2, tenascin C, fibroblast growth factor-1 and -2, connective tissue growth factor and interleukin-6 expression in wild type osteoblasts, but not PAR-1 null mouse osteoblasts. Induction of all the thrombin-responsive genes was blocked by the presence of the non-selective cyclooxygenase inhibitor indomethacin. Further studies were conducted on interleukin-6, which was the gene that showed the greatest increase in expression following stimulation of osteoblast-like cells with thrombin. A PAR-1-specific activating peptide, but neither a PAR-4-activating peptide nor catalytically inactive thrombin induced release of interleukin-6 by osteoblasts. Furthermore, in the presence of the selective cyclooxygenase-1 and -2 inhibitors SC-560 and NS-398 thrombin-induced interleukin-6 release was prevented. Levels of both prostaglandin E(2) and interleukin-6 in medium conditioned by thrombin-stimulated osteoblast-like cells were found to be significantly increased compared to medium conditioned by non-stimulated cells, however release of prostaglandin E(2) was found to precede release of interleukin-6. Treatment of isolated osteoblast-like cells with a number of synthetic prostanoids stimulated secretion of interleukin-6 with differing potencies. These studies suggest that activation of PAR-1 on osteoblasts by thrombin induces cyclooxygenase activity, which in turn results in the increased expression of multiple secreted factors. The induction of these secreted factors may act in an autocrine fashion to alter osteoblast function, allowing these cells to participate in the earliest stages of bone healing by both autocrine and paracrine mechanisms.
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PMID:Thrombin-stimulated growth factor and cytokine expression in osteoblasts is mediated by protease-activated receptor-1 and prostanoids. 1944 25


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