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Nakaizumi A Horie T Kida T Kurimoto T Sugiyama T Ikeda T Oku H 《Cellular and molecular neurobiology》2012,32(1):95-106
Modulation of enzyme activity through nitrosylation has recently been identified as a new physiological activity of nitric
oxide (NO). We hypothesized that NO enhances the TNF-α-induced death of retinal neurons through a suppression of nuclear factor-κB
(NF-κB) by nitrosylation. In this study, cells from the RGC-5 line were exposed to different concentrations (2.0, 10, and
50 ng/ml) of TNF-α, and the degree of TNF-α-induced cell death was determined by the WST-8 assay and by flow cytometric measurements
of the externalization of phosphatidylserine. The effects of etanercept, a soluble TNFR-Fc fusion protein, and S-nitroso-N-penicillamine (SNAP), an NO donor, on the toxicity were determined. Experiments were also performed to determine whether
nitric oxide synthase (NOS) was associated with the toxicity of TNF-α. The activation of NF-κB was determined by the detection
of the p65 subunit in the nuclear extracts. Our results showed that exposure of RGC-5 cells to different concentrations of
TNF-α significantly decreased the number of living cells in a dose-dependent way. The death was partially due to apoptosis
with an externalization of phosphatidylserine, and the death was suppressed by etanercept. Exposure to TNF-α increased the
activation of NF-κB and the expression of iNOS. Although NF-κB inhibitors suppressed the increase of iNOS, they also potentiated
the TNF-α-induced death. Both L-NAME and aminoguanidine, both NOS inhibitors, rescued the cells from death. In contrast, addition
of SNAP caused nitrosylation of the inhibitory κB kinase, and suppressed the NF-κB activation and potentiated the TNF-α-induced
neurotoxicity. These results indicate that NO potentiates the neurotoxicity of TNF-α by suppressing NF-κB. 相似文献
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Changes in the levels of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) protein has been reported in murine and human tuberculosis.
We investigated the role of mitogen-activated protein kinase pathways in the production of Bcl-2 protein in THP-1 human monocytes
infected with Mycobacterium tuberculosis H37Rv and H37Ra. Analysis of phosphorylation profiles of mitogen-activated protein kinase kinase-1, extracellular-signal
regulated kinase 1/2, mitogen-activated protein kinase kinase 3/6, and p38 mitogen-activated protein kinase; B-cell lymphoma
2 kinetics; and tumor necrosis factor-α (TNF-α) secretion levels showed variation between the two strains. Mycobacterium tuberculosis H37Rv induced higher Bcl-2 and lower TNF-α levels, whereas H37Ra the reverse. The strains also differed in their usage of
CD14 and human leukocyte antigen-DR receptors in mediating extracellular-signal regulated kinase 1/2 and p38 mitogen-activated
protein kinase activation. Mycobacterium tuberculosis H37Rv- and H37Ra-induced Bcl-2 production was reduced by specific inhibitors of mitogen-activated protein kinase kinase-1
(PD98059) and p38 (SB203580), but increased by nuclear factor κB (NF-κB) inhibitor (BAY 11-7082). TNF-α production by both
strains was reduced in the presence of specific inhibitors of mitogen-activated protein kinase kinase-1 (PD98059), p38 (SB203580),
and NF-κB (BAY 11-7082). Furthermore, inhibition of NF-κB was accompanied by an increase in strain-induced extracellular-signal
regulated kinase 1/2 phosphorylation. Collectively, these results indicate for the first time that the production of Bcl-2
and TNF-α by M. tuberculosis H37Rv/H37Ra-infected THP-1 human monocytes is mediated through mitogen-activated protein kinases and NF-κB. 相似文献
4.
Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway 总被引:2,自引:0,他引:2
Huang TH Li Y Razmovski-Naumovski V Tran VH Li GQ Duke CC Roufogalis BD 《Journal of biomedical science》2006,13(4):535-548
Summary Nuclear factor (NF)-κB is important in the generation of inflammation. Besides regulating lipid metabolism, peroxisome proliferator-activated receptor (PPAR)-α activators also reduce NF-κB activation to terminate activation of inflammatory pathways. Gynostemma pentaphyllum (GP) has been used to treat various inflammatory diseases and hyperlipidemia. Here, we demonstrate that GP extract and one of its main components, Gypenoside XLIX (Gyp-XLIX) inhibited LPS-induced NF-κB activation in murine macrophages. Furthermore, Gyp-XLIX restored the LPS- and TNF-α-induced decrease in cytosolic I-κBα protein expression and inhibited the translocation of NF-κB(p65) to the nucleus in THP-1 monocyte and HUVEC cells. The inhibition of LPS- and TNF-α-induced NF-κB luciferase activity in macrophages was abolished by MK-886, a selective PPAR-α antagonist. GP extract and Gyp-XLIX (EC50: 10.1 μM) enhanced PPAR-α luciferase activity in HEK293 cells transfected with the tK-PPREx3-Luc reporter plasmid and expression vectors for PPAR-α. Additionally, Gyp-XLIX specifically enhanced PPAR-α mRNA and protein expression in THP-1-derived macrophage cells. The selectivity of Gyp-XLIX for PPAR-α was demonstrated by the activation of only PPAR-α in HEK293 cells transfected with expression vectors for PPAR-α, PPAR-β/δ or PPAR-γ1 plasmids and in THP-1-derived macrophage naturally expressing all three PPAR isoforms. The present study demonstrates that Gyp-XLIX, a naturally occurring gynosaponin, inhibits NF-κB activation via a PPAR-α-dependent pathway.Tom Hsun-Wei Huang and Yuhao Li contributed equally. 相似文献
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3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of renal disease
independent of cholesterol-lowering effect, but the mechanism of potential protective effect remains unclear. Here, we investigate
the effect of fluvastatin on activation of nuclear factor-κB (NF-κB) induced by angiotensin II (AngII) in rat kidney tubule
epithelial cells (NRK-52E). Electrophoretic mobility shift assays (EMSA) was used to detect NF-κB activation. Phosphorylation
of cellular p38 mitogen-activated protein kinase (p38MAPK) was determined by western blot analysis. AngII stimulated the DNA-binding
activity of NF-κB and phosphorylation of p38MAPK in cultured NRK-52E cells in a dose-dependent (10−9–10−6 mol/l) manner (P < 0.01). AngII (10−6 mol/l) induced a rapid (5 min) increase of the p38MAPK phosphorylation. NF-κB DNA-binding activity was increased at as early
as 30 min, peaked at 2 h after AngII treatment. This stimulatory effect of AngII on NF-κB was blocked by SB203580 (a specific
inhibitor of p38MAPK). Incubation of cells with fluvastatin significantly inhibited the AngII-induced NF-κB activation in
a dose-dependent (10−7–10−5 mol/l) manner (P < 0.05). Exogenous mevalonate (10−4mol/l) prevented the effect of fluvastatin on NF-κB activation. These results suggest the fluvastatin reduced AngII-induced
NF-κB activation via the p38MAPK pathway in NRK-52E cells. The effect is at least partly due to blocking the biosynthesis
of mevalonate. 相似文献
6.
Johanna Westra Berber Doornbos-van der Meer Peter de Boer Miek A van Leeuwen Martin H van Rijswijk Pieter C Limburg 《Arthritis research & therapy》2004,6(4):R384
In inflammatory processes, the p38 mitogen-activated protein kinase (MAPK) signal transduction route regulates production
and expression of cytokines and other inflammatory mediators. Tumor necrosis factor α (TNF-α) is a pivotal cytokine in rheumatoid
arthritis and its production in macrophages is under control of the p38 MAPK route. Inhibition of the p38 MAPK route may inhibit
production not only of TNF-α, but also of other inflammatory mediators produced by macrophages, and indirectly of inflammatory
mediators by other cells induced by TNF-α stimulation. Here we investigate the effects of RWJ 67657, a p38 MAPK inhibitor,
on mRNA expression and protein production of TNF-α and other inflammatory mediators, in monocyte-derived macrophages. A strong
inhibition of TNF-α was seen at pharmacologically relevant concentrations of RWJ 67657, but also inhibition of mRNA expression
of IL-1β, IL-8, and cyclooxygenase-2 was shown. Furthermore, it was shown that monocyte-derived macrophages have a high constitutive
production of matrix metalloproteinase 9, which is not affected by p38 MAPK inhibition. The results presented here may have
important implications for the treatment of rheumatoid arthritis. 相似文献
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Sunahori K Yamamura M Yamana J Takasugi K Kawashima M Yamamoto H Chazin WJ Nakatani Y Yui S Makino H 《Arthritis research & therapy》2006,8(3):R69-12
S100A8 and S100A9, two Ca2+-binding proteins of the S100 family, are secreted as a heterodimeric complex (S100A8/A9) from neutrophils and monocytes/macrophages.
Serum and synovial fluid levels of S100A8, S100A9, and S100A8/A9 were all higher in patients with rheumatoid arthritis (RA)
than in patients with osteoarthritis (OA), with the S100A8/A9 heterodimer being prevalent. By two-color immunofluorescence
labeling, S100A8/A9 antigens were found to be expressed mainly by infiltrating CD68+ macrophages in RA synovial tissue (ST). Isolated ST cells from patients with RA spontaneously released larger amounts of
S100A8/A9 protein than did the cells from patients with OA. S100A8/A9 complexes, as well as S100A9 homodimers, stimulated
the production of proinflammatory cytokines, such as tumor necrosis factor alpha, by purified monocytes and in vitro-differentiated macrophages. S100A8/A9-mediated cytokine production was suppressed significantly by p38 mitogen-activated
protein kinase (MAPK) inhibitors and almost completely by nuclear factor kappa B (NF-κB) inhibitors. NF-κB activation was
induced in S100A8/A9-stimulated monocytes, but this activity was not inhibited by p38 MAPK inhibitors. These results indicate
that the S100A8/A9 heterodimer, secreted extracellularly from activated tissue macrophages, may amplify proinflammatory cytokine
responses through activation of NF-κB and p38 MAPK pathways in RA. 相似文献
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The mechanism by which lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) induces production of proinflammatory
cytokines in murine macrophages, and the role of phosphatidylinositol 3-kinase (PI3-kinase) have not been well investigated.
Activation of nuclear factor κB (NF-κB) is initiated by the phosphorylation of the inhibitory subunit, IκB, which targets
IκB for degradation and leads to the release of active NF-κB. In this study we demonstrate that 2- (4-morpholinyl)-8-phenylchromone
(LY294002), which inhibits PI3-kinase, specifically inhibited degradation of IκBα in RAW264.7 cells stimulated with interferon-γ
(IFN-γ) plus LPS or IFN-γ plus PMA. To elucidate the importance of this activity in RAW264.7 cells, we examined tumor necrosis
factor-α (TNF-α) and interleukin IL)-6 production in the activated cells. Pretreatment of the cells with LY294002 resulted
in the inhibition of TNF-α and IL-6 production in RAW264.7 cells stimulated with IFN-γ plus LPS or IFN-γ plus PMA. Furthermore,
LY294002 inhibited the production of nitric oxide NO) in RAW264.7 cells stimulated with IFN-γ plus LPS or IFN-γ plus PMA.
LY294002 also inhibited inducible NO synthase (iNOS) mRNA expression in the activated RAW264.7 cells. In conclusion, the present
results suggest that PI3-kinase is involved in the signal transduction pathway responsible for LPS- or PMA-mediated TNF-α
and IL-6 production, and that LY294002 inhibits NO generation through blocking the degradation of IκBα in activated RAW264.7
cells.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
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Effects of glutamine on the nuclear factor-kappaB signaling pathway of murine peritoneal macrophages
Marcelo Macedo Rogero Primavera Borelli Ricardo Ambrósio Fock Maria Carolina Borges Marco Aurélio Ramirez Vinolo Rui Curi Karina Nakajima Amanda Rabello Crisma Aline Domingas Ramos Julio Tirapegui 《Amino acids》2010,39(2):435-441
The aim of this study was to evaluate the effect of glutamine on the expression of proteins involved in the nuclear factor-kappaB
(NF-κB) signaling pathway of murine peritoneal macrophages. Since glutamine is essential for the normal functioning of macrophages,
it was hypothesized that in vitro glutamine supplementation would increase NF-κB activation. Peritoneal macrophages were pretreated
with glutamine (0, 0.6, 2 and 10 mM) before incubation with lipopolysaccharide (LPS), and the effects of glutamine on the
production of tumor necrosis factor-alpha and on the expression and activity of proteins involved in the NF-κB signaling pathway
were studied by an enzyme linked immuno-sorbent assay, Western blotting, and an electrophoretic mobility shift assay. Glutamine
treatment (2 and 10 mM) increased the activation of NF-κB in LPS-stimulated peritoneal macrophages (P < 0.05). In non-stimulated cells, glutamine treatment (2 and 10 mM) significantly reduced IκB-α protein expression (P < 0.05). Glutamine modulates NF-κB signaling pathway by reducing the level of IκB-α, leading to an increase in NF-κB within
the nucleus in peritoneal macrophages. 相似文献
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Morchella conica is a species of rare edible mushroom whose multiple medicinal functions have been proven. However, reports barely mention
the mechanisms of these functions. In this study, the effects of two polysaccharides from M. conica (PMCs) on nitric oxide (NO) production in lipopolysaccharide (LPS)-treated macrophages were investigated. The results showed
that 50–200 μg/ml of the extracellular polysaccharide (EPMC) and 25–200 μg/ml of the intracellular polysaccharide (IPMC) significantly
inhibited NO production. Accordingly, the signal mechanisms were also explored. It was found that 100 μg/ml of EPMC and 25 μg/ml
of IPMC could efficiently down-regulate the inducible nitric oxide synthase (iNOS) expression and nuclear factor-κB (NF-κB)
DNA-binding activity and up-regulate heme oxygenase 1 (HO-1) expression. Moreover, by using a HO-1 inhibitor NaPP to treat
the cells, the PMC-inhibited NO production and iNOS expression, rather than NF-κB activation, were released partially, indicating
that HO-1 probably medicates the inhibition of PMCs on iNOS and NO. Besides, EPMC also significantly suppressed the phosphorylation
of p38 mitogen-activated protein kinase (p38), c-jun N-terminal kinase, mitogen-activated protein kinase kinase 4, and expression
of NF-κB inducing kinase, while IPMC seemed to show no regular effect on p38. In conclusion, PMCs inhibited NO production
in LPS-induced macrophages through regulating a series of signal pathways, suggesting that PMCs play a potential role on immunomodulation
and treating related diseases. 相似文献
16.
Rainer Voisard Nicola Huber Regine Baur Milorat Susa Oliver Ickrath Anton Both Wolfgang Koenig Vinzenz Hombach 《BMC molecular biology》2001,2(1):7-7
Background
Activation of nuclear factor-κB (NF-κB) is one of the key events in early atherosclerosis and restenosis. We hypothesized that tumor necrosis factor-α (TNF-α) induced and NF-κB mediated expression of intercellular adhesion molecule-1 (ICAM-1) can be inhibited by antisense RelA p65 and NF-κB1 p50 oligonucleotides (RelA p65 and NF-κB1 p50). 相似文献17.
H2 is a therapeutic antioxidant that can reduce oxidative stress. Oxidized low-density lipoprotein, which plays roles in atherosclerosis,
may promote endothelial dysfunction by binding the cell-surface receptor LOX-1. LOX-1 expression can be upregulated by various
stimuli, including TNF-α. Thus, we aimed to examine whether the upregulation of LOX-1 by different stimuli could be blocked
by H2 in endothelial cells. H2 significantly abolished the upregulation of LOX-1 by different stimuli, including TNF-α, at the protein and mRNA levels.
The TNF-α-induced upregulation of LOX-1 was also attenuated by the NF-κB inhibitor N-acetyl-l-cysteine. H2 inhibited the TNF-α-induced activation of NF-κB and the phosphorylation of IκB-α. Furthermore, H2 inhibited the expression of LOX-1 and the activation of NF-κB in apolipoprotein E knockout mice, an animal model of atherosclerosis.
Thus, H2 probably inhibits cytokine-induced LOX-1 gene expression by suppressing NF-κB activation. 相似文献
18.
Sander W Tas Margriet J Vervoordeldonk Najat Hajji Michael J May Sankar Ghosh Paul P Tak 《Arthritis research & therapy》2006,8(4):R86-9
Nuclear factor (NF)-κB is a key regulator of synovial inflammation. We investigated the effect of local NF-κB inhibition in
rat adjuvant arthritis (AA), using the specific IκB kinase (IKK)-β blocking NF-κB essential modulator-binding domain (NBD)
peptide. The effects of the NBD peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as rheumatoid
arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD peptide on RA FLS
in vitro. Subsequently, NBD peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease.
The severity of arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for
routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD peptides, and cytokine production was measured in the supernatant by enzyme-linked immunosorbent
assay. The NBD peptide blocked interleukin (IL)-1-β-induced IκBα phosphorylation and IL-6 production in RA FLS. Intra-articular
injection of the NBD peptide led to significantly reduced severity of arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of tumor necrosis factor (TNF)-α
and IL-1-β in the synovium. Incubation of human macrophages with NBD peptides resulted in 50% inhibition of IL-1-β-induced
TNF-α production in the supernatant (p < 0.01). In addition, the NBD peptide decreased TNF-α-induced IL-6 production by human RA synovial tissue biopsies by approximately
42% (p < 0.01). Specific NF-κB blockade using a small peptide inhibitor of IKK-β has anti-inflammatory effects in AA and human RA
synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate
that IKK-β-targeted NF-κB blockade using the NBD peptide could offer a new approach for the local treatment of arthritis. 相似文献
19.
P38 mitogen-activated protein kinases (p38 MAPK) and tumor necrosis factor-α (TNF-α) play important roles in oxidative stress-induced
apoptosis in cardiac myocytes. However, the regulation and functional role of cross-talk between p38 MAPK and TNF-α pathways
have not yet been fully characterized in cardiac myocytes. In this study, we found that inhibition of p38 MAPK with SB-203580
(SB) reduced H2O2-stimulated secretion of TNF-α, whereas pre-activation of p38 MAPK with sodium arsenite (SA) enhanced H2O2-stimulated secretion of TNF-α. In addition, pretreatment of cells with TNF-α increased basal and H2O2-stimulated p38 MAPK and apoptosis of cardiac myocytes, and p38 MAPK-associated apoptosis of cardiac myocytes induced by TNF-α
was blocked by inhibition of p38 MAPK with SB. Finally, H2O2-induced apoptosis was attenuated by the inhibitors of p38 MAPK or reactive oxygen species (ROS), whereas it was enhanced
by p38 MAPK agonist SA. These results suggest that H2O2-induced secretion of TNF-α increases apoptosis of cardiac myocytes through ROS-dependent activation of p38 MAPK. This may
represent a novel mechanism that TNF-α partly interplays with p38 MAPK pathways during oxidative stress-modulated apoptosis
in cardiac myocytes. 相似文献