Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:021712 (IL-6)
 58,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A proinflammatory cytokine cascade, including IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8, is activated in response to infection or immunologic insult. Besides their immunologic effects, several of these mediators stimulate bone resorption and inhibit bone formation. Osteocalcin, the most abundant noncollagenous protein present in bone, is an osteoblast-specific product whose production closely correlates with bone formation, and which has also been implicated in control of bone resorption. IL-1 and TNF have previously been shown to down-regulate osteocalcin production in vitro and in vivo, although the mechanism of this inhibition is unknown. In the present studies, IL-1 beta and TNF-alpha both inhibited 1,25-dihydroxyvitamin D3-stimulated production of osteocalcin protein and mRNA by ROS 17/2.8 osteosarcoma cells, whereas IL-6 had no effect on protein and only weakly inhibited mRNA. To determine if down-regulation was exerted at the transcriptional level, an osteocalcin promoter-chloramphenicol acetyltransferase (CAT) fusion gene was constructed (PHOC-CAT). After transient transfection of PHOC-CAT into ROS 17/2.8 osteosarcoma cells, reporter CAT activity was up-regulated by vitamin D at concentrations above 10(-12) M. In screening studies, TNF-alpha (-57%) and IL-6 (-37%) inhibited vitamin D-stimulated osteocalcin transcription, whereas IL-1 alpha, IL-1 beta, and IL-8 had no effect. Other immune cytokines and growth factors, including IL-2, IL-3, IL-7, and M-CSF, also failed to regulate osteocalcin transcription. Despite their lack of promoter regulation, IL-1 alpha and IL-1 beta also stimulated PGE2 production by ROS 17/2.8, further confirming the ability of the host cell to respond to these mediators. In dose-response experiments, down-regulation by TNF-alpha was significant at concentrations as low as 0.14 pM (0.1 U/ml), whereas approximately 10(4)-fold higher concentration of IL-6 was required to exert a similar effect. TNF-alpha-mediated down-regulation was unaffected by indomethacin. These data demonstrate that of these cytokines, TNF-alpha alone potently down-regulates osteocalcin promoter function, whereas IL-1 acts post-transcriptionally, possibly by reducing mRNA stability. Heterogeneity therefore exists among the proinflammatory cytokines with respect to the level at which control of osteocalcin expression is exerted.
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PMID:Proinflammatory cytokines tumor necrosis factor-alpha and IL-6, but not IL-1, down-regulate the osteocalcin gene promoter. 130 41

Evidence has accumulated over the past 20 years to implicate paramyxoviruses in the etiopathology of Paget's disease. In the USA, the predominant virus detected is MV, whereas in northwestern England, CDV is most prevalent. The viruses are known to be easily spread by aerosol transmission to the respiratory tissues, from which they gain entry to the skeletal tissues via the hematopoietic system. Another characteristic of these viruses is their ability to persist at very low levels, thus evading the host immune response. Further studies have shown that IL-6, c-fos, and Bcl-2 are all elevated in Paget's disease--all of these factors can be activated by virally induced ROS. The genetic predisposition to Paget's disease and the perplexing focal nature of the disorder can also be explained by viral infection. Finally, the bisphosphonates, the class of drugs used so successfully to treat Paget's disease, have been shown to act, at least in part, by counteracting two of the major effects of the viruses in Paget's disease. The weight of evidence in support of a viral etiology for Paget's disease is overwhelming.
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PMID:Paramyxoviruses and Paget's disease: the affirmative view. 1032 21

Parathyroid hormone (PTH) is a promising anabolic agent for the treatment of osteoporosis. However, PTH is also potently catabolic. To help delineate the molecular mediators of PTH's opposing effects on skeletal metabolism, we have examined PTH-induced regulator of G-protein signaling-2 (RGS-2) expression and function in murine osteoblasts. RGS proteins are GTPase-activating proteins (GAPs) that regulate GTP-binding protein-coupled receptor (GPCR) signaling by enhancing the intrinsic GTPase activity of Galpha subunits. We found that 10 nmol/L PTH maximally induced RGS-2 mRNA in murine MC3T3-E1 cells, rat Py1a and ROS-17/2.8 cells, primary mouse osteoblasts (MOB cells), and mouse calvariae organ culture at 1-2 h posttreatment. PTH signaling through its receptor, PTHR1, is coupled to cAMP-protein kinase A (PKA), protein kinase C (PKC), and calcium signaling pathways. We examined the effect of selective signaling agonists and antagonists on RGS-2 expression in MOB cells to determine which pathway(s) mediates PTH-induced RGS-2 expression. Although selective activation of all three pathways led to RGS-2 expression, cAMP-PKA activation with 10 nmol/L PTH and 10 micromol/L forskolin elicited the strongest induction. Similarly, RGS-2 mRNA expression was most strongly inhibited by the PKA inhibitor, H89 (10-30 micromol/L). The phorbol ester, PMA (1 micromol/L), which activates the PKC pathway, and ionomycin (1 micromol/L), which activates the calcium pathway, produced small but detectable elevations in RGS-2 mRNA levels. Overnight treatment with 1 micromol/L PMA to deplete PKC did not affect subsequent RGS-2 induction by PTH, but significantly inhibited PMA-induced RGS-2 expression. Treatment with 1-100 nmol/L PTH(3-34), which does not activate cAMP-PKA signaling, did not induce RGS-2 expression. MOB cells pretreated with 3 microg/mL cycloheximide produced sustained RGS-2 mRNA levels 2 h after 10 nmol/L PTH treatment. Actinomycin D (5 microg/mL) completely blocked 10 nmol/L PTH-induced RGS-2 expression. Finally, we tested the effect of RGS-2 overexpression on PTH- and fluprostenol-induced interleukin (IL)-6 promoter activity in MOB cells. PTH induces IL-6 through PKA activation, whereas fluprostenol induces IL-6 through PKC activation. We found that RGS-2 overexpression significantly inhibited IL-6 promoter activity following fluprostenol treatment, but not following PTH treatment. We conclude that RGS-2 is a PTH-induced primary response gene in murine osteoblasts that is induced mainly through the cAMP-PKA pathway and specifically inhibits Galphaq-coupled receptors.
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PMID:Parathyroid hormone induces RGS-2 expression by a cyclic adenosine 3',5'-monophosphate-mediated pathway in primary neonatal murine osteoblasts. 1199 4

In this study, we investigated the effects of proteasome inhibibors (MG132 and lactacystin) on interleukin (IL)-8 induction. In human epithelial A549 cells, MG132 and lactacystin induced IL-8 release within the range of 0.1-30 microM. The effect of MG132 resulted from IL-8 gene transcription and was blocked by PD 98059, but was unaffected by GF109203X, Ro 31-8220, or SB 203580. Mutational analysis of the 5' flanking region of the IL-8 gene revealed that activator protein (AP)-1-binding element, but not that element responsive to nuclear factor (NF)-IL-6 or NF-kappaB, was necessary for MG132 stimulation. Consistent with this, MG132 and lactacystin increased the DNA-binding and reporter activities of AP-1, but reduced cytokine-elicited kappaB activation. Moreover, AP-1 stimulation was associated with increased extracellular signal-related kinase (ERK), mitogen-activated protein/ERK kinase (MEK), and c-Jun N-terminal kinase (JNK) phosphorylation, whereas IL-8 activity was sensitive to the dominant-negative mutants of JNK1, JNK2, SEK, ASK, ERK2, and Ras, but not those of MEKK1, TAK, and p38 mitogen-activated protein kinase. In addition, activations of the IL-8 gene and AP-1 by MG132 and lactacystin were inhibited by GSH and NAC. Herein we present a novel action of proteasome inhibitors, possibly through ROS production, of targeting the upstream signaling molecules, ERK and JNK, which leads to AP-1 activation and IL-8 gene expression.
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PMID:Proteasome inhibitors stimulate interleukin-8 expression via Ras and apoptosis signal-regulating kinase-dependent extracellular signal-related kinase and c-Jun N-terminal kinase activation. 1215 16

cAMP/PKA signaling transiently stimulates mRNA expression of immediate-early genes, including IL-6 and c-fos. We confirmed that these mRNAs are transiently stimulated by parathyroid hormone (PTH) in ROS 17/2.8 osteoblastic cells. Consistent with the role for cAMP/PKA signaling in this response, PTH induces transient cAMP elevation, PKA activation, and cAMP-responsive element-binding protein (CREB) phosphorylation. Our goal was to determine whether termination of immediate-early gene expression is due to receptor desensitization or cAMP degradation. The approaches used were 1) inhibition of PTH receptor desensitization with G protein-coupled receptor kinase 2 (GRK2) antisense oligonucleotides or antisense plasmids, 2) sustained activation of adenyl cyclase with forskolin, and 3) inhibition of cAMP degradation with 3-isobutyl-1-methylxanthine. These experiments show that mechanisms downstream of receptor desensitization and cAMP degradation are primarily responsible for termination of PKA activity, CREB phosphorylation, and immediate-early gene expression. Similar conclusions were also obtained in response to PTH in a second osteoblastic cell line (MC3T3-E1) and in response to isoproterenol in NIH3T3 fibroblasts. This conclusion may therefore reflect a general mechanism for termination of immediate-early gene expression after induction by cAMP/PKA.
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PMID:Termination of immediate-early gene expression after stimulation by parathyroid hormone or isoproterenol. 1237 4

Cytokines form a kind of regulatory net which normal functioning is critical for development of inflammation and regeneration in eye, namely cornea. In connection with this, we studied effects of complex of natural cytokine obtained from pig and comprising activities of IL-1, IL-6, TNF, MIF, TGFbeta1, on post-burn regeneration in rabbit cornea. The cornea burn was induced by 10% NaOH and cytokine complex was locally administered (over month after the burn) to the regeneration site observed as wall-eye. Hystologic analysis and in vitro experiment with mice (F1 hybrids of CBAxC57BL) peritoneal macrophages and human peripheral blood neutrophils were performed to reveal cytokine biological roles. CC augmented post-burn cornea regeneration that is distinctly observed at all regeneration stages and manifested as: (i) action on macrophages at the early regeneration (inhibition of migration, activation of phagocytosis, ROS production, cytokine synthesis and secretion); and (ii) attraction of cornea stromal cells to the regeneration site and enhancement of their main functions (proliferation, fibronectin and collagen synthesis). As a consequence of CC local administration, post-burn regeneration site displayed high plasticity, low scaring and vascularization, being close to those of normal tissue, that finally enabled progression of successful keratoplastics. The data reported below show wide perspectives for administration of natural cytokine complex to treat cornea alterations of various genesis.
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PMID:Complex of Natural Cytokines Regulate Post-Burn Regeneration in Cornea. 1268 86

This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.
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PMID:Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. 1292 88

Antimicrobial agents have been reported to exhibit immunomodulatory and anti-inflammatory activities, both in vivo and in vitro (e.g., in human lymphocytes, macrophages and monocytes). The effects of moxifloxacin on cytokine immunomodulatory mediators, free radical generation and hydrolytic enzyme activities in zymogen A-stimulated human THP-1 monocytes were evaluated. An increase in c-AMP levels, protein kinase C activity, and the release of nitric oxide and hydrogen peroxide with a decrease in pH occurred within the first hour. Further, the effects of moxifloxacin were reduced by agents which blocked the oxygen burst, lysosome-phagosome fusion, and the energy generation within the cell. After 4 h, there was a decrease in NAG and cathepsin D activities, lipid peroxidation and the release of pro-inflammatory cytokines. These data indicate that moxifloxacin may modify the acute-phase inflammatory responses through inhibition of cytokine release in monocytes. Moxifloxacin inhibited the release of TNFalpha, IL-1, IL-6, and IL-8 in a concentration-dependent manner across a range of 0.004 to 4 microg/mL. After 4 h, there was a decrease in the release of these cytokines, thus interfering with the inflammation process to reduce infection and its spread. The effects of moxifloxacin appear initially to activate monocytes to kill bacteria through the innate immune process by releasing ROS and lysosomal hydrolytic enzymes as well as phagocytosis of the organism. At a later time the bacteria are killed through a Bacterialstatic mechanism of protein synthesis inhibition and there is a reversal of the effects of moxifloxacin on cytokine release, free radical generation and hydrolytic enzymes so that lipid peroxidation and tissue destruction by the infection process is suppressed.
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PMID:Effects of moxifloxacin in zymogen A or S. aureus stimulated human THP-1 monocytes on the inflammatory process and the spread of infection. 1367 36

Epidemiologic evidence in humans suggests a role for selenium in reducing cancer incidence and mortality. The aim of the present study was that to assess the ability of selenium dioxide (SeO2) to enhance the lymphocyte progression through the cell cycle in patients with advanced (stage IV) cancer. Ten patients (mean age 51.9 years, range: 32-74; M/F ratio: 3/7) with tumors at different sites were included in the study. The addition into culture of SeO2 1.5 microM enhanced significantly the progression into S phase of PBMCs isolated from cancer patients, whilst no significant effect was observed on PBMCs isolated from controls. ROS levels were significantly higher, whereas GPx activity was significantly lower in cancer patients than controls. Serum levels of IL-6 and TNFalpha were significantly higher in cancer patients than controls. Our results show the ability of selenium to induce a progression of PBMCs from cancer patients into the cell cycle, which is an essential prerequisite for the physiological functioning of the immune system and thus positively influence the immune status of advanced cancer patients. The mechanism of action of selenium could be to downregulate the production and release of proinflammatory cytokines, which have a role in cancer progression and particularly in the onset of cachexia.
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PMID:Selenium is effective in inducing lymphocyte progression through cell cycle in cancer patients: potential mechanisms for its activity. 1525 93

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
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PMID:Increased oxidative stress in obesity and its impact on metabolic syndrome. 1559


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