UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Hydroxynonenal (HNE), a lipid peroxidation end product, is produced abundantly in osteoarthritic (OA) articular tissues, but its role in bone metabolism is ill-defined. In this study, we tested the hypothesis that alterations in OA osteoblast metabolism are attributed, in part, to increased levels of HNE. Our data showed that HNE/protein adduct levels were higher in OA osteoblasts compared to normal and when OA osteoblasts were treated with H2O2. Investigating osteoblast markers, we found that HNE increased osteocalcin and type I collagen synthesis but inhibited alkaline phosphatase activity. We next examined the effects of HNE on the signaling pathways controlling cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) expression in view of their putative role in OA pathophysiology. HNE dose-dependently decreased basal and tumour necrosis factor-alpha (TNF-alpha)-induced IL-6 expression while inducing COX-2 expression and prostaglandin E2 (PGE2) release. In a similar pattern, HNE induces changes in osteoblast markers as well as PGE2 and IL-6 release in normal osteoblasts. Upon examination of signaling pathways involved in PGE2 and IL-6 production, we found that HNE-induced PGE2 release was abrogated by SB202190, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Overexpression of p38 MAPK enhanced HNE-induced PGE2 release. In this connection, HNE markedly increased the phosphorylation of p38 MAPK, JNK2, and transcription factors (CREB-1, ATF-2) with a concomitant increase in the DNA-binding activity of CRE/ATF. Transfection experiments with a human COX-2 promoter construct revealed that the CRE element (-58/-53 bp) was essential for HNE-induced COX-2 promoter activity. However, HNE inhibited the phosphorylation of IkappaBalpha and subsequently the DNA-binding activity of nuclear factor-kappaB. Overexpression of IKKalpha increased TNF-alpha-induced IL-6 production. This induction was inhibited when TNF-alpha was combined with HNE. These findings suggest that HNE may exert multiple effects on human OA osteoblasts by selective activation of signal transduction pathways and alteration of osteoblastic phenotype expression and pro-inflammatory mediator production.
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PMID:Alterations of metabolic activity in human osteoarthritic osteoblasts by lipid peroxidation end product 4-hydroxynonenal. 1704 56

We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. The Hsp90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) upregulated protein expression and phosphorylation of Hsp27; conversely, BIRB 796 inhibited this phosphorylation and enhanced 17-AAG-induced cytotoxicity. Importantly, BIRB 796 inhibited Hsp27 phosphorylation induced by 17-AAG plus bortezomib, thereby enhancing cytotoxicity. In bone marrow stromal cells (BMSC), BIRB 796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor triggered by either tumour necrosis factor-alpha or tumour growth factor-beta1. BIRB 796 also inhibited IL-6 secretion induced in BMSCs by adherence to MM cells, thereby inhibiting tumour cell proliferation. These studies therefore suggest that BIRB 796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90 inhibitor, or Dex, to improve patient outcome in MM.
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PMID:BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. 1717 46

It is unclear whether cardiac hypertrophy and hypertrophy-related pathways will be induced by long-term intermittent hypoxia. Thirty-six Sprague-Dawley rats were randomly assigned into three groups: normoxia, and long-term intermittent hypoxia (12% O(2), 8 h per day) for 4 weeks (4WLTIH) or for 8 weeks (8WLTIH). Myocardial morphology, trophic factors and signalling pathways in the three groups were determined by heart weight index, histological analysis, Western blotting and reverse transcriptase-polymerase chain reaction from the excised left ventricle. The ratio of whole heart weight to body weight, the ratio of left ventricular weight to body weight, the gross vertical cross-section of the heart and myocardial morphological changes were increased in the 4WLTIH group and were further augmented in the 8WLTIH group. In the 4WLTIH group, tumour necrosis factor-alpha(TNFalpha), insulin-like growth factor (IGF)-II, phosphorylated p38 mitogen-activated protein kinase (P38), signal transducers and activators of transcription (STAT)-1 and STAT-3 were significantly increased in the cardiac tissues. However, in the 8WLTIH group, in addition to the above factors, interleukin-6, mitogen-activated protein kinase (MEK)5 and extracellular signal-regulated kinase (ERK)5 were significantly increased compared with the normoxia group. We conclude that cardiac hypertrophy associated with TNFalpha and IGF-II was induced by intermittent hypoxia. The longer duration of intermittent hypoxia further activated the eccentric hypertrophy-related pathway, as well as the interleukin 6-related MEK5-ERK5 and STAT-3 pathways, which could result in the development of cardiac dilatation and pathology.
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PMID:Eccentric cardiac hypertrophy was induced by long-term intermittent hypoxia in rats. 1718 50

In patients with chronic heart failure (CHF) increased plasma concentrations of proinflammatory cytokines are found. For example, the plasma interleukin-6 (IL-6) concentration correlates with disease severity. Beside IL-6 cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is also increased in CHF. We examined whether CT-1 is able to induce IL-6 in human umbilical vein endothelial cells (HUVEC) and characterised the underlying pathway. IL-6 mRNA was determined by real-time PCR and by RT-PCR in HUVEC which were stimulated with different CT-1 concentrations and for different time periods. IL-6 concentration in the supernatant was determined by ELISA. For the pathway determination following inhibitors were used: piceatannol (signal transducer and activation of transcription (STAT)3 phosphorylation), wortmannin (phosphatiylinositol 3-kinase (PI3K)), SB203580 (p38 mitogen-activated protein kinase (MAPK)), AG490 (Janus kinase (JAK)2), PD98059 (mitogen-activated protein kinase kinase (MEK) 1/2), parthenolide (nuclear factor kappaB) and cycloheximide (protein biosynthesis). CT-1 caused a concentration- and time-dependent increase in IL-6 mRNA in HUVEC with a maximal induction seen after 6 h (2-fold compared to control) with 100 ng/ml CT-1. In the supernatant of HUVEC a concentration- and time-dependent increase of IL-6 protein was found. A maximum effect with 100 ng/ml CT-1 was found after 24 h (11-fold compared to control). AG490, SB203580, piceatannol, parthenolide and cycloheximide inhibit CT-1 induced IL-6 mRNA and protein expression whereas wortmannin and PD98059 did not inhibit IL-6 expression. CT-1 induced both IL-6 mRNA and protein in a concentration- and time-dependent manner in HUVEC. The underlying pathway includes activation of JAK2, STAT3, p38 and NFkappaB. CT-1 induced IL-6 expression and requires protein synthesis and IL-6 is not stored intracellularly. We speculate that in CHF CT-1 might be in part responsible for increased IL-6 plasma concentrations. Modulation of the CT-1 pathway may be a further strategy in CHF treatment.
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PMID:Cardiotrophin-1 induces interleukin-6 synthesis in human umbilical vein endothelial cells. 1719 93

We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204+/-4 mm Hg, but partially reduced after BIRB796 treatment (166+/-7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The beta-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-alpha, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-alpha expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage.
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PMID:p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. 1722 70

The release of proinflammatory cytokines after mycobacterial infection is a host immune response that may be propitious or deleterious to the host. Elevated levels of interleukin (IL)-6 are present in plasma of patients with active tuberculosis infection. The aim of this study was to investigate the role of mitogen-activated protein kinases in the secretion of interleukin-6 in THP-1 cells and human primary monocytes that were infected with Mycobacterium tuberculosis H37Rv, and its regulation by N-acetyl-L-cysteine, a potential antimycobacterial agent. Exposure of THP-1 human monocytes to M. tuberculosis H37Rv induced rapidly, in a time-dependent manner, the phosphorylation of mitogen-activated protein kinase kinase 3/6 and p38 mitogen-activated protein kinase, accompanied by an upregulation of interleukin-6. Using highly specific inhibitors of mitogen-activated protein kinase kinase-1, p38 mitogen-activated protein kinase and nuclear factor-kappaB, we found that extracellular-signal regulated kinase 1/2, p38 mitogen-activated protein kinase and nuclear factor-kappaB were essential for M. tuberculosis H37Rv-induced interleukin-6 production in human primary monocytes. Pretreatment with N-acetyl-L-cysteine reduced, in a dose-dependent manner, M. tuberculosis H37Rv-induced activation of mitogen-activated protein kinase kinase 3/6 and interleukin-6 production in THP-1 cells.
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PMID:Mycobacterium tuberculosis H37Rv induces monocytic release of interleukin-6 via activation of mitogen-activated protein kinases: inhibition by N-acetyl-L-cysteine. 1752 93

Despite the essential role of the fibrinogen gamma-chain as a blood clotting factor, the fibrinogen gamma-chain contains a number of interaction sites to recruit other factors such as leukocytes important for prevention of pathogen entry and propagation of the repair process. Interleukin-6 (IL-6) is known as the major inducer of gamma-fibrinogen synthesis in hepatocytes, whereas IL-1beta has been shown to act as a potent inhibitor of gamma-fibrinogen expression. Studies on the rat fibrinogen gamma-chain promoter suggest that nuclear factor (NF)-kappaB replaces the signal transducer and activator of transcription (STAT) 3 from binding to overlapping NF-kappaB/STAT3 binding sites within the 5' regulatory region of the rat gamma-chain gene promoter. However, despite its physiological relevance, the underlying mechanism responsible for the inhibitory effect of IL-1beta in humans is still not understood and apparently more complex. In contrast to the mechanism described for the rat gene our results indicate that IL-1beta suppresses the IL-6-induced activation of the human gamma-fibrinogen gene particularly by blocking the late phase STAT3-tyrosine phosphorylation NF-kappaB-dependently but independent from de novo protein synthesis. Consequently, blocking NF-kappaB activation restores specifically late phase STAT3 activation as well as the induction of the human gamma-fibrinogen gene. In contrast, specifically early STAT3 activation could be restored by a block of the p38 mitogen-activated protein kinase (p38(MAPK)) pathway. In summary, our results indicate that expression of the gamma-fibrinogen gene is mainly controlled by the strength of late phase STAT3 activation, which in turn is negatively regulated by the extent of IL-1beta-mediated NF-kappaB activity.
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PMID:Activation of NF-kappaB by IL-1beta blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human gamma-fibrinogen gene. 1754

Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-kappaB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.
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PMID:Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells. 1759 97

Plasminogen activator inhibitor-1 (PAI-1) plays a pivotal role in the regulation of the fibrinolytic system and in the modulation of extracellular proteolysis. Increased PAI-1 was found in atherosclerotic lesions, and high PAI-1 plasma levels were associated with coronary heart disease. Smooth muscle cells (SMC) are a major source of PAI-1 within the vascular wall, and PAI-1 was implicated in SMC migration, proliferation, and apoptosis. We treated human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) with the glycoprotein 130 (gp130) ligands cardiotrophin-1, interleukin-6 (IL-6), leukemia inhibitory factor (LIF), or oncostatin M (OSM). Only OSM increased PAI-1 antigen and activity production significantly in these cells up to 20-fold. OSM upregulated mRNA specific for PAI-1 up to 4.5-fold in these cells. HCASMC and HASMC express gp130, OSM receptor, IL-6 receptor, and LIF receptor. OSM induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylations in HASMC. A phosphatidylinositol 3-kinase inhibitor and a mitogen-activated protein/extracellular signal-regulated kinase inhibitor reduced Akt and ERK1/2 phosphorylation, respectively, and abolished OSM-induced PAI-1 upregulation. A janus kinase/signal transducer and activator of transcription inhibitor, a p38 mitogen-activated protein kinase inhibitor, or c-Jun NH(2)-terminal kinase inhibitor I did not inhibit the OSM-dependent PAI-1 induction. OSM enhanced proliferation of both HCASMC and HASMC by 77 and 90%, respectively. We hypothesize that, if the effect of OSM on PAI-1 expression in smooth muscle cells is operative in vivo, it could, via modulation of fibrinolysis and extracellular proteolysis, be involved in the development of vascular pathologies such as plaque progression, destabilization and subsequent thrombus formation, and restenosis and neointima formation.
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PMID:The inflammatory cytokine oncostatin M induces PAI-1 in human vascular smooth muscle cells in vitro via PI 3-kinase and ERK1/2-dependent pathways. 1760 27

Previous studies have suggested that cathepsin B participates in the joint destruction associated with rheumatoid arthritis (RA). This study examined the activity of cathepsin B (a lysosomal cysteine protease) in human osteoblasts along with its regulation by cyclic AMP and Interleukin-6 (IL-6). Cyclic AMP elevating agents activate cathepsin B and stimulate the secretion of cathepsin B via the secretion of IL-6, a potent mediator of RA. This study investigated the induction of cathepsin B using the proinflammatory cytokine in human osteoblasts (MG-63) in relation to p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B transcription factor. When added to MG-63 cells, IL-6 stimulated the production of cathepsin B, which was reduced significantly by the addition of SB203580, a specific p38 MAPK inhibitor. In addition, the release of IL-6 was also inhibited by either pyrrolidine dithiocarbamate (PDTC) or NF-kappaB SN50, which are potent NF-kappaB inhibitors. Both NF-kappaB inhibitors had a larger inhibitory effect on the activity of cathepsin B in the presence of SB203580. IL-6 stimulated the NF-kappaB binding affinity as well as the activation of p38 MAP kinase, leading to the release of cathepsin B. However, SB203580 had no effect on the IL-6-induced activation of NF-kappaB, and neither of the NF-kappaB inhibitors decreased the level of p38 MAPK activation in the IL-6-stimulated osteoblasts. Moreover, IL-6 increased the activity of urokinase type plasminogen activator (uPA) in MG-63 cells, which was inhibited by SB203580, PDTC and NF-kappaB SN50. This strongly suggests that p38 MAPK and NF-kappaB are essential to the IL-6-induced activation of cathepsin B or uPA and that these two IL-6-activated pathways can act independently.
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PMID:Interleukin-6 and cyclic AMP stimulate release of cathepsin B in human osteoblasts. 1784 65

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