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1.
Fei Guo Yuanlei Lou Nianhua Feng Guohui Li An Xie Xueming Huang Yang Wang 《Biometals》2010,23(4):669-680
Lanthanum chloride, a rare earth compound, possesses antibacterial and cellular immunity regulating properties. However, the
underlying molecular mechanisms remain largely unknown. In this study, we examined the effects of lanthanum chloride on the
production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α), the expression of inducible NO synthase (iNOS) and TNF-α
in RAW 264.7 cells, a mouse macrophage cell line. We found that the LPS-elicited excessive production of NO and TNF-α in RAW
264.7 cells was inhibited significantly in the presence of lanthanum chloride, and the attenuation of iNOS and TNF-α occurred
at mRNA level. Furthermore, the possible signaling components affected by lanthanum chloride in the pathway that lead to LPS-induced
iNOS and TNF-α expression were explored. The results indicated the involvements of PKC/Ca2+ and NF-κB in the attenuation of NO and pro-inflammatory cytokine production by lanthanum chloride. Our observations suggest
a possible therapeutic application of this agent for treating inflammatory diseases. 相似文献
2.
Extracellular ATP and adenosine modulation of MAPKs is well described in different cells types, but few studies have addressed the effects of extracellular inosine on these kinases. Previous results showed that hydrogen peroxide and TNF-alpha increase extracellular inosine concentration in cultured Sertoli cells and this nucleoside protects Sertoli cells against hydrogen peroxide induced damage and participates in TNF-alpha induced nitric oxide production. In view of the fact that MAPKs are key mediators of the cellular response to a large variety of stimuli, we investigated the effect of extracellular inosine on the phosphorylation of ERK 1/2 and p38 MAPKs in cultured Sertoli cells. The involvement of this nucleoside in the activation of ERK 1/2 by TNF-alpha was also investigated. Inosine and the selective A1 adenosine receptor agonist R-PIA increases the phosphorylation of ERK 1/2 and p38, and this was blocked by the selective A1 adenosine receptors antagonists, CPT and DPCPX. These antagonists also inhibited TNF-alpha increase in the phosphorylation of ERK 1/2. TNF-alpha also rapidly augmented extracellular inosine concentration in cultured Sertoli cells. These results show that extracellular inosine modulates ERK 1/2 and p38 in cultured Sertoli cells, possible trough A1 adenosine receptor activation. This nucleoside also participates in TNF-alpha modulation of ERK 1/2. 相似文献
3.
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
4.
5.
The failure of chondrocytes to replace the lost extracellular matrix contributes to the progression of degenerative disorders
of cartilage. Inflammatory mediators present in the joint regulate the breakdown of the established matrix and the synthesis
of new extracellular matrix molecules. In the present study, we investigated the effects of tumor necrosis factor alpha (TNF-α)
and epidermal growth factor (EGF) on chondrocyte morphology and matrix gene expression. Chondrocytes were isolated from distal
femoral condyles of neonatal rats. Cells in primary culture displayed a cobblestone appearance. EGF, but not TNF-α, increased
the number of cells exhibiting an elongated morphology. TNF-α potentiated the effect of EGF on chondrocyte morphology. Individually,
TNF-α and EGF diminished levels of aggrecan and type II collagen mRNA. In combination, the effects of TNF-α and EGF were additive,
indicating the involvement of discrete signaling pathways. Cell viability was not compromised by TNF-α or by EGF, alone or
in combination. EGF alone did not activate NF-κB or alter NF-κB activation by TNF-α. Pharmacologic studies indicated that
the effects of TNF-α and EGF alone or in combination were independent of protein kinase C signaling, but were dependent on
MEK1/2 activity. Finally, we analyzed the involvement of Sox-9 using a reporter construct of the 48 base pair minimal enhancer
of type II collagen. TNF-α attenuated enhancer activity as expected; in contrast, EGF did not alter either the effect of TNF-α
or basal activity. TNF-α and EGF, acting through distinct signaling pathways, thus have additive adverse effects on chondrocyte
function. These findings provide critical insights into the control of chondrocytes through the integration of multiple extracellular
signals. 相似文献
6.
Cheng C Qin Y Shao X Wang H Gao Y Cheng M Shen A 《Cellular and molecular neurobiology》2007,27(7):909-921
Mitogen-activated protein kinases (MAPKs) are important mediators of cytokine expression and are critically involved in the
immune response. The lipopolysaccharide (LPS) of gram-negative bacteria induces the expression of cytokines and proinflammatory
genes via the toll-like receptor 4 (TLR4) signaling pathway in diverse cell types. In vivo, Schwann cells (SCs) at the site
of injury may also produce tumor necrosis factor-- α (TNF-α). However, the precise mechanisms of TNF-α synthesis are still
not clear. The purpose of the present study was to elucidate the underlying molecular mechanisms in the cultured SCs for its
ability to activate the MAPKs and TNF-α gene, in response to LPS. Using enzyme-linked immunosorbent assay (ELISA), it was
confirmed that treatment with LPS stimulated the synthesis of TNF-α in a concentration- and time-dependent manner. Intracellular
location of TNF-α was detected under confocal microscope. Moreover, LPS activated extracellular signal-regulated kinase (ERK1/2),
P38 and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and induced their phosphorylation. LPS-elicited
SCs TNF-α production was also drastically suppressed by PD98059 (ERK inhibitor), SB202190 (P38 inhibitor), or SP600125 (SAPK/JNK
inhibitor). Additionally, the expression of CD14 and TLR4 was examined by RT–PCR. It was demonstrated that the expression
of CD14, TLR4 was crucial for the SCs responses to LPS. In conclusion, the results provide novel mechanisms for the response
of SCs to LPS stimulation, through MAPKs signaling pathways.
Chun Cheng and Yongwei Qin contributed equally to this work. 相似文献
7.
The present study attempts to investigate the effects of S-propargyl-cysteine (SPRC), a sulfur-containing amino acid, on lipopolysaccharide (LPS)-induced inflammatory response in H9c2
cardiac myocytes. We found that SPRC prevented nuclear factor-κB (NF-κB) activation assessed by NF-κB p65 phosphorylation
and IκBα degradation, suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and intracellular
reactive oxygen species (ROS) production. Furthermore, incubation of H9c2 cells with SPRC induced phosphorylation of Akt in
a time- and concentration-dependent manner. In addition, SPRC attenuated LPS-induced mRNA and protein expression of tumor
necrosis factor-α (TNF-α), and mRNA expression of intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase
(iNOS). The effects of SPRC were abolished by cystathionine γ-lyase [CSE-an enzyme that synthesizes hydrogen sulfide (H2S)] inhibitor, dl-propargylglycine (PAG), SPRC-induced Akt phosphorylation and TNF-α release was also abolished by the phosphoinositide 3-kinase
(PI3K) inhibitor LY294002. Furthermore, SPRC also increased LPS-induced down-regulation expression of CSE and H2S level in H9c2 cells. PAG abolished SPRC-induced up-regulation of H2S level. Therefore, we concluded that SPRC produced an anti-inflammatory effect in LPS-stimulated H9c2 cells partly through
the CSE/H2S pathway by impairing IκBα/NF-κB signaling and by activating PI3K/Akt signaling pathway. 相似文献
8.
Shen A Zhou D Shen Q Liu HO Sun L Liu Y Chen J Yang J Ji Y Cheng C 《Neurochemical research》2009,34(2):333-341
The proinflammatory and lipopolysaccharide (LPS)-inducible cytokine tumor necrosis factor α (TNF-α) has been shown to enhance
primary sensory nociceptive signaling. However, the precise cellular site of TNF-α synthesis is still a matter of controversy.
Therefore, we focused our study on TNF-α protein synthesis and expression patterns in spinal dorsal horn of naives and rats
under intrathecal challenge with LPS. The enzyme-linked immunosorbent (ELISA) assay showed that the protein level of TNF-α
reached peak at 8 h. Double immunofluorescence revealed that LPS-induced expression of TNF-α exclusively located in a subpopulation
of microglia, which increased at 8 h in the rat spinal dorsal horn (the injected side). Positive staining of TNF receptor
1 (TNFR1) were also found in microglia. These observations have demonstrated the production of this proinflammatory cytokine
by central nerve glia especially microglia. Synthesized TNF-α might directly act on microglia via TNFR1, but the inherent
mechanisms remain unknown. Further studies are needed to confirm the pathogenic role of tumor necrosis factor in the early
stage of inflammation.
Aiguo Shen and Dan Zhou contributed equally to this work. 相似文献
9.
Bernhard Metzler Johannes Jehle Igor Theurl Susanne Ludwiczek Peter Obrist Otmar Pachinger Günter Weiss 《Biometals》2007,20(2):205-215
The role of iron in the pathogenesis of cardio-vascular disorders is still controversial. We studied the effects of iron perturbations
on myocardial injury upon temporary ischemia/reperfusion. C57BL/6J male mice were injected with iron dextran for 2 weeks while
controls received saline. Mice were then subjected to 30 min of myocardial ischemia and subsequent reperfusion for 6–24 h.
Tissue damage was quantified histologically and by troponin T determination. The expressions of tumor necrosis factor-α (TNF-α),
superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were investigated in non-ischemic and ischemic regions
of both groups. After myocardial ischemia and reperfusion, troponin T levels, as a marker of myocardial damage, were significantly
reduced in iron-treated mice as compared to control mice (P < 0.05). Under the same conditions the infarction area and damage score were significantly lower in iron-treated animals.
In parallel, TNF-α and SOD expressions were increased in infarcted regions of iron-treated mice as compared to controls, whereas
myocardial iNOS expression was significantly lower in iron-treated mice. Although, iron challenge increased radical formation
and TNF-α expression in vivo, this did not result in myocardial damage which may be linked to the parallel induction of SOD. Importantly, iron treatment
inhibited iNOS expression. Since, an increased nitric oxide (NO) formation has been linked to cardiac damage after acute myocardial
infarction, iron may exert short time cardio-protective effects after induction of ischemia/reperfusion via decreasing iNOS
formation.
Both authors contributed equally to this work. 相似文献
10.
Tumor necrosis factor-α (TNF-α) is a polypeptide cytokine that has been associated with muscle wasting and weakness in inflammatory disease. Despite its potential importance in muscle pathology, the direct effects of TNF-α on skeletal muscle have remained undefined until recently. Studies of cultured muscle cells indicate that TNF-α disrupts the differentiation process and can promote catabolism in mature cells. The latter response appears to be mediated by reactive oxygen species and nuclear factor-κB which upregulate ubiquitin/proteasome activity. This commentary outlines our current understanding of TNF-α effects on skeletal muscle and the mechanism of TNF-α action. 相似文献
11.
This review discusses the functional role of nitric oxide in ischemia-reperfusion injury and mechanisms of signal transduction
of apoptosis, which accompanies ischemic damage to organs and tissues. On induction of apoptosis an interaction is observed
of the nitric oxide signaling system with the sphingomyelin cycle, which is a source of a proapoptotic agent ceramide. Evidence
is presented of an interaction of the sphingomyelin cycle enzymes and ceramide with nitric oxide and enzymes synthesizing
nitric oxide. The role of a proinflammatory cytokine TNF-α in apoptosis and ischemia-reperfusion and mechanisms of its cytotoxic
action, which involve nitric oxide, the sphingomyelin cycle, and lipid peroxidation are discussed. A comprehensive study of
these signaling systems provides insight into the molecular mechanism of apoptosis during ischemia and allows us to consider
new approaches for treatment of diseases associated with the activation of apoptosis. 相似文献
12.
Culturing hepatocytes with a combination of LPS, TNF-α, IL-1β and IFN-γ resulted in an inhibition of glucose output from glycogen
and prevented the repletion of glycogen in freshly cultured cells. The reduced glycogen mobilisation correlated with the lower
cell glycogen content and reduced rate of glycogen synthesis from [U-14C]glucose rather than alterations in either total phosphorylase or phosphorylase a activity. There was no change in the percentage
of glycogen exported as glucose nor the production of lactate plus pyruvate indicating that redistribution of the Gluc-6-P
cannot explain the failure of the liver to export glucose. Although changes in glycogen mobilisation correlated with NO production,
inhibition of NO synthase by inclusion of L-NMMA in the culture medium failed to prevent the inhibition of either glycogen
accumulation or mobilisation by the proinflammatory cytokines, precluding the involvement of NO in this response. LPS plus
cytokine treatment had no effect on total glycogen synthase activity although the activity ratio was lowered, indicative of
increased phosphorylation. The inhibition of glycogen synthesis correlated with a fall in the intracellular concentrations
of Gluc-6-P and UDP-glucose and in the absence of measured changes in kinase activity, it is suggested that the fall in Gluc-6-P
reduces both substrate supply and glycogen synthase phosphatase activity. The fall in Gluc-6-P coincided with a reduction
in total glucokinase and hexokinase activity within the cells, but no significant change in either the translocation of glucokinase
or glucose-6-phosphatase activity. This demonstrates direct cytokine effects on glycogen metabolism independent of changes
in glucoregulatory hormones. 相似文献
13.
14.
Akihiko Hiyama Katsuya Yokoyama Tadashi Nukaga Daisuke Sakai Joji Mochida 《Arthritis research & therapy》2013,15(6):R189
Introduction
Increased expression of the proinflammatory cytokine TNF-α in intervertebral discs (IVDs) leads to inflammation, which results in progressive IVD degeneration. We have previously reported that activation of Wnt-β-catenin (hereafter called Wnt) signaling suppresses the proliferation of nucleus pulposus cells and induces cell senescence, suggesting that Wnt signaling triggers the process of degeneration of the IVD. However, it is not known whether cross talk between TNF-α and Wnt signaling plays a role in the regulation of nucleus pulposus cells. The goal of the present study was to examine the effect of the interaction between Wnt signaling and the proinflammatory cytokine TNF-α in nucleus pulposus cells.Methods
Cells isolated from rat nucleus pulposus regions of IVDs were cultured in monolayers, and the expression and promoter activity of Wnt signaling and TNF-α were evaluated. We also examined whether the inhibition of Wnt signaling using cotransfection with Dickkopf (DKK) isoforms and Sclerostin (SOST) could block the effects of pathological TNF-α expression in nucleus pulposus cells.Results
TNF-α stimulated the expression and promoter activity of Wnt signaling in nucleus pulposus cells. In addition, the activation of Wnt signaling by 6-bromoindirubin-3′-oxime (BIO), which is a selective inhibitor of glycogen synthase kinase 3 (GSK-3) activity that activates Wnt signaling, increased TNF-α expression and promoter activity. Conversely, the suppression of TNF-α promoter activity using a β-catenin small interfering RNA was evident. Moreover, transfection with DKK-3, DKK-4, or SOST, which are inhibitors of Wnt signaling, blocked Wnt signaling-mediated TNF-α activation; these effects were not observed for DKK-1 or DKK-2.Conclusions
Here, we have demonstrated that Wnt signaling regulates TNF-α and that Wnt signaling and TNF-α form a positive-feedback loop in nucleus pulposus cells. The results of the present study provide in vitro evidence that activation of Wnt signaling upregulates the TNF-α expression and might cause the degeneration of nucleus pulposus cells. We speculate that blocking this pathway might protect nucleus pulposus cells against degeneration. 相似文献15.
16.
A comparative study was done using J774A.1 and J774A. 1-derived transfected cells (J774A.1 C.1) containing antisense tumor
necrosis factor α (TNF-α) plasmid to determine the role of endogenous TNF-α on nitric oxide production as well as on the growth
ofMycobacterium microti in interferon γ (IFN-γ)- and lipopolysaccharide (LPS)-treated cells. On stimulation with IFN-γ and LPS a higher level of
NO was observed in J774A.1 cells compared to J774A.1 C.1 which indicated that endogenous TNF-α is required for the production
of NO. Comparing the effect of IFN-γ and LPS on the intracellular growth ofM. microti, the growth-reducing activity was higher in J774A.1 cells than in J774A.1 C.1 cells and was not completely abrogated in the
presence of the nitric oxide inhibitorN
G-methyl-l-arginine (l-NMA). J774A.1 C.1 cells infected withM. microti produced a significant amount of NO when exogenous TNF-α was added along with IFN-γ and LPS and the concentration of intracellular
bacteria decreased almost to that in IFN-γ and LPS treated parental J774A.1 cells. Addition of exogenous TNF-α even in the
presence ofl-NMA in J774.1 C.1 cells could also partially restore intracellular growth inhibition ofM. microti caused by IFN-γ and LPS. TNF-α is probably required for the production of NO in J774A.1 cells by IFN-γ and LPS but TNF-α
and NO are independently involved in the killing of intracellularM. microti with IFN-γ and LPS. 相似文献
17.
Glutathione depletion is accompanied by increased neuronal nitric oxide synthase activity 总被引:3,自引:0,他引:3
The effect of glutathione depletion, in vivo, on rat brain nitric oxide synthase activity has been investigated and compared
to the effect observed in vitro with cultured neurones. Using L-buthionine sulfoximine rat brain glutathione was depleted
by 62%. This loss of glutathione was accompanied by a significant increase in brain nitric oxide synthase activity by up to
55%. Depletion of glutathione in cultured neurones, by approximately 90%, led to a significant 67% increase in nitric oxide
synthase activity, as judged by nitrite formation, and cell death. It is concluded that depletion of neuronal glutathione
results in increased nitric oxide synthase activity. These findings may have implications for our understanding of the pathogenesis
of neurodegenerative disorders in which loss of brain glutathione is considered to be an early event. 相似文献
18.
Inhibition of Inducible Nitric Oxide Synthase Expression by Endothelin in Rat Glial Cells Prepared from the Neonatal Rat Brain 总被引:1,自引:0,他引:1
Abstract: In primary cultured rat glial cells, a combination of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) stimulates production of nitrite via expression of the inducible form of nitric oxide synthase (iNOS). In these cells, simultaneous addition of endothelin (ET) decreased iNOS expression and nitrite accumulation induced by TNF-α/IL-1β. The inhibitory effect of ET on TNF-α/IL-1β-stimulated iNOS expression appears to be mediated by ETB receptors, because (1) both ET-1 and ET-3 inhibited the effects of TNF-α/IL-1β on iNOS expression and nitrite accumulation, (2) a selective ETB receptor agonist, Suc-[Glu9 ,Ala11,15 ]-ET-1 (8–21) (IRL1620), decreased the effects of TNF-α/IL-1β, and (3) a selective ETB receptor antagonist, N-cis -2,6-dimethylpiperidinocarbonyl- l -γ-methylleucyl- d -1-methoxycarbonyltryptophanyl- d -norleucine, abolished the inhibitory effects of ETs and IRL1620. Incubation of glial cells with lipopolysaccharide (LPS) caused an increase in iNOS expression. Simultaneous addition of ET-3 decreased the effects of LPS (10 and 100 ng/ml) on iNOS expression. Furthermore, cyclic AMP-elevating agents (dibutyryl cyclic AMP and forskolin) inhibited TNF-α/IL-1β-induced and LPS-induced iNOS expression and nitrite accumulation. These findings suggest that ETs can decrease TNF-α/IL-1β-induced and LPS-induced iNOS expression via ETB receptors and that cyclic AMP may be involved in this process. 相似文献
19.
Diabetic patients reveal significant disorders, such as nephropathy, cardiomyopathy, and neuropathy. As oxidative stress and
inflammation seem to be implicated in the pathogenesis of diabetic brain, we aimed to investigate the effects of caffeic acid
phenethyl ester (CAPE) on oxidative stress and inflammation in diabetic rat brain. Diabetes was induced by a single dose of
streptozotocin (45 mg kg−1, i.p.) injection into rats. Two days after streptozotocin treatment 10 μM kg−1 day−1 CAPE was administrated and continued for 60 days. Here, we demonstrate that CAPE significantly decreased the levels of nitric
oxide and malondialdehyde induced by diabetes, and the activities of catalase, glutathione peroxidase, and xanthine oxidase
in the brain. However, glutathione levels were increased by CAPE. The mRNA expressions of tumor necrosis factor (TNF)-α and
interferon (IFN)-γ, and inducible nitric oxide synthase (iNOS) were remarkably enhanced in brain by diabetes. CAPE treatments significantly suppressed these inflammatory cytokines
(about 70% for TNF-α, 26% for IFN-γ) and NOS (completely). Anti-inflammatory cytokine IL-10 mRNA expression was not affected
by either diabetes or CAPE treatments. In conclusion, diabetes induces oxidative stress and inflammation in the brain, and
these may be contributory mechanisms involved in this disorder. CAPE treatment may reverse the diabetic-induced oxidative
stress in rat brains. Moreover, CAPE reduces the mRNA expressions of TNF-α and IFN-γ in diabetic brain; suggesting CAPE suppresses
inflammation as well as oxidative stress occurred in the brain of diabetic patients. 相似文献
20.
Lactosylceramide (LacCer) is a member of the glycosphingolipid family which has been recently recognized as a signaling intermediate
in the regulation of cell proliferation and cell adhesion. In this paper, we present our studies pointing to a potential role
of LacCer in inducing apoptosis. In our studies we employed a human osteosarcoma cell line MG-63 (wild type, WT) and a neutral
sphingomyelinase (N-SMase) deficient cell line CC derived from MG-63 (mutant) cells. We observed that WT cells were highly
sensitive to tumor necrosis factor-α (TNF-α), ceramide and LacCer-induced apoptosis. In contrast, the mutant cells were insensitive
to TNF-α-induced apoptosis as they did not generate ceramide and LacCer. However, the exogenous supply of ceramide and/or
LacCer rendered the mutant cells apoptotic. Interestingly, preincubation of cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol
(D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase, abrogated ceramide-induced apoptosis but
not LacCer-induced apoptosis in both WT cells and the mutant cells. Moreover, TNF-α and LacCer-induced apoptosis required
the generation of reactive oxygen species (ROS) in WT cells. However, since mutant cells did not produce significant amounts
of LacCer and ROS in response to TNF-α treatment they are insensitive to TNF-α-induced apoptosis. In summary, our studies
suggest that TNF-α-induced N-SMase activation and production of ceramide is required to activate the apoptosis pathway in
human osteosarcoma cells. But it is not sufficient to induce apoptosis. Rather, the conversion of ceramide to LacCer and ROS
generation are critical for apoptosis. 相似文献