nfkb1 - nuclear factor of kappa light polypeptide enhancer in B-cells
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Pubmed
Journal: Zhongguo shi yan xue ye xue za zhi
September/29/2011
Abstract
This study was purposed to investigate the relationship between activation of nuclear factor-κB (NF-κB) and multidrug resistance in K562/AO₂ cells and its mechanism. Human erythroleukemic cell line K562 and its adriamycin-resistant counterpart K562/AO₂ cells were used in the study. After inhibiting the activation of NF-κB with noncytotoxic concentration of antioxidant pyrrolidine dithiocarbamate (PDTC) in vitro, the multiple of drug resistance of K562/AO₂ cells was assessed by MTT assay. RT-PCR and flow cytometry method were used to detect the relative expression of mdr-1 mRNA and P-gp, respectively. The results showed that (1) multidrug resistance of K562/AO₂ cells to ADM was 59 times higher than that of K562 cells. When being pretreated with 0.2 μmol/L PDTC which is noncytotoxic to cells, the IC₅₀ of ADM in K562/AO₂ cells was sharply decreased with relative reverse efficiency of 93.03%, which was more higher than that of classic modifying agents Verapamil (Ver); (2) NF-κB activity of K562/AO₂ cells was significantly higher than that of K562 cells (p < 0.01). When being treated with PDTC, the activation of NF-κB was sharply decreased in K562/AO₂ cells; with 0.2 μmol/L PDTC for 24 hours it decreased to the lowest, nearly to the K562 cell level (p > 0.05); (3) the relative expression of both mdr-1 mRNA and P-gp in K562/AO₂ cells was more higher; the expressions of mdr-1 mRNA and P-gp both were inhibited in K562/AO₂ cell group treated with PDTC for 48 hours. It is concluded that the PDTC used as an inhibitor of NF-κB activity can partially reverse the multidrug resistance of K562/AO₂ cells, which mechanism can be associated with the down-regulation of mdr-1 mRNA and P-gp.
Pubmed
Journal: Neoplasia (New York, N.Y.)
March/2/2014
Abstract
Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-κB. Recent studies have highlighted the importance of NF-κB activation as a key pathogenic mechanism in glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults.We examined the expression of TRADD by immunohistochemistry (IHC) and find that TRADD is commonly expressed at high levels in GBM and is detected in both cytoplasmic and nuclear distribution. Cytoplasmic IHC TRADD scoring is significantly associated with worse progression-free survival (PFS) both in univariate and multivariate analysis but is not associated with overall survival (n = 43 GBMs). PFS is a marker for responsiveness to treatment. We propose that TRADD-mediated NF-κB activation confers chemoresistance and thus a worse PFS in GBM. Consistent with the effect on PFS, silencing TRADD in glioma cells results in decreased NF-κB activity, decreased proliferation of cells, and increased sensitivity to temozolomide. TRADD expression is common in glioma-initiating cells. Importantly, silencing TRADD in GBM-initiating stem cell cultures results in decreased viability of stem cells, suggesting that TRADD may be required for maintenance of GBM stem cell populations. Thus, our study suggests that increased expression of cytoplasmic TRADD is both an important biomarker and a key driver of NF-κB activation in GBM and supports an oncogenic role for TRADD in GBM.
Pubmed
Journal: Annals of human genetics
October/9/2006
Abstract
It is well-known that baseline levels of C-reactive protein (CRP) are an independent cardiovascular risk factor. We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system. We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes (CARD15, IRAK1, IRAK4, LBP, LY86, MEFV, TLR2, TLR4 and NFKB1) in relation to CRP levels. Seven hundred and seventeen subjects from the Women's Health Study population were studied: 359 and 358 samples with extremely low (<0.2 mg/liter) and high (>5 mg/liter) CRP levels, respectively. SNPs were identified from publicly available resequencing data, using a minor allele frequency threshold of >5% and a linkage disequilibrium (LD)-based strategy (r(2) > 0.8) to select 63 LD-independent markers. One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied. Univariate, haplotype and gene-gene interaction analyses all indicated no significant association with CRP levels. Although this work excludes a significant association of common SNPs in these nine genes with CRP levels, it is possible that rarer alleles in these genes, or variation in other innate immunity genes, could be associated with variation in CRP.
Pubmed
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
November/10/2013
Abstract
OBJECTIVE
The presence of TNF-α in approximately 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. Inhibitor of IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways.
METHODS
Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197 on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo.
RESULTS
13-197 inhibited the kinase activity of IKKβ in vitro and TNF-α-mediated NF-κB transcription in cells with low-μmol/L potency. 13-197 inhibited the phosphorylation of IκBα, S6K, and eIF4EBP, induced G1 arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity.
CONCLUSIONS
These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic.
Pubmed
Journal: Journal of virology
July/30/1997
Abstract
The avian leukosis virus (ALV) long terminal repeat (LTR) contains a compact transcription enhancer that is active in many cell types. A major feature of the enhancer is multiple CCAAT/enhancer element motifs that could be important for the strong transcriptional activity of this unit. The contributions of the three CCAAT/enhancer elements to LTR function were examined in B cells, as this cell type is targeted for ALV tumor induction following integration of LTR sequences next to the c-myc proto-oncogene. One CCAAT/enhancer element, termed a3, was found to be the most critical for LTR enhancement in transiently transfected B lymphoma cells, while in chicken embryo fibroblasts all three elements contributed equally to enhancement. Gel shift assays demonstrated that vitellogenin gene-binding protein (VBP), a member of the PAR subfamily of C/EBP factors, is a major component of the nuclear proteins binding to the a3 CCAAT/enhancer element. VBP activated transcription through the a3 CCAAT/enhancer element, supporting the idea that VBP is important for LTR enhancement in B cells. A member of the Rel family of proteins was also identified as a component of the a3 protein binding complex in B cells. Gel shift and immunoprecipitation assays indicated that this factor is RelA. Gel shift assays demonstrated that while RelA does not bind directly to the LTR CCAAT/enhancer elements, it does interact with VBP to potentiate VBP DNA binding activity. The synergistic interaction of VBP and RelA increased CCAAT/enhancer element-mediated transcription, indicating that both factors may be important for viral LTR regulation and also for expression of many cellular genes.
Pubmed
Journal: Journal of neurochemistry
January/2/2008
Abstract
Signaling by the p75 neurotrophin receptor (p75) has been implicated in diverse neuronal responses, including the control of neuronal survival versus death and axonal regeneration and growth cone collapse, involving p75 in different neuropathological conditions. There are different levels of complexity regulating p75-mediated signaling. First, p75 can interact with different ligands and co-receptors in the plasma membrane, forming tripartite complexes, whose activation result in different cellular outcomes. Moreover, it was recently described that trafficking capacities of p75 in neurons are regulating, in addition to p75 downstream interactions, also the sequential cleavage of p75. The proteolytical processing of p75 involves, first, a shedding event that releases a membrane-bound carboxiterminal fragment (p75-CTF), followed by a gamma-secretase mediated cleavage, generating a soluble intracellular domain (p75-ICD) with signaling capabilities. The first shedding event, generating a p75-CTF, is the key step to regulating the production of p75-ICD, and although the generation of p75-ICD is important for both p75-mediated control of neuronal survival and the control of neurite outgrowth, little is known how both cleavage events are regulated. In this review, we argue that both sheddases and gamma-secretase are key membrane components regulating p75-mediated signaling transduction; therefore, further attention should be paid to their roles as p75 signaling regulators.
Pubmed
Journal: The Journal of biological chemistry
August/27/2015
Abstract
The NF-κB transcriptional response is tightly regulated by a number of processes including the phosphorylation, ubiquitination, and subsequent proteasomal degradation of NF-κB subunits. The IκB family protein BCL-3 stabilizes a NF-κB p50 homodimer·DNA complex through inhibition of p50 ubiquitination. This complex inhibits the binding of the transcriptionally active NF-κB subunits p65 and c-Rel on the promoters of NF-κB target genes and functions to suppress inflammatory gene expression. We have previously shown that the direct interaction between p50 and BCL-3 is required for BCL-3-mediated inhibition of pro-inflammatory gene expression. In this study we have used immobilized peptide array technology to define regions of BCl-3 that mediate interaction with p50 homodimers. Our data show that BCL-3 makes extensive contacts with p50 homodimers and in particular with ankyrin repeats (ANK) 1, 6, and 7, and the N-terminal region of Bcl-3. Using these data we have designed a BCL-3 mimetic peptide based on a region of the ANK1 of BCL-3 that interacts with p50 and shares low sequence similarity with other IκB proteins. When fused to a cargo carrying peptide sequence this BCL-3-derived peptide, but not a mutated peptide, inhibited Toll-like receptor-induced cytokine expression in vitro. The BCL-3 mimetic peptide was also effective in preventing inflammation in vivo in the carrageenan-induced paw edema mouse model. This study demonstrates that therapeutic strategies aimed at mimicking the functional activity of BCL-3 may be effective in the treatment of inflammatory disease.
Pubmed
Journal: Biochimica et biophysica acta
September/11/2007
Abstract
Constitutive active NF-kappaB have been shown to protect cutaneous T cell lymphoma (CTCL) cells from apoptosis. In the present study, we have studied the cytotoxic potential of nitric oxide generating compound, sodium nitroprusside (SNP) on CTCL cell line, HuT-78. Treatment of cells with SNP resulted in decrease in mitochondrial membrane potential, cytochrome c release, activation of caspase-3 and poly (ADP ribose) polymerase cleavage. SNP treatment inhibited activation of NF-kappaB in a concentration dependent manner. SNP increased the expression of IkappaBalpha without affecting the phosphorylation of IkappaBalpha. Downregulation of NF-kappaB by SNP decreased p65 nuclear translocation as evident by confocal fluorescence microscopy. Further it was found that SNP treatment caused downregulation of Bcl-2 family member (Bcl-xl) in HuT-78 cells. Thus, we have provided evidence that SNP induces apoptosis in CTCL cell line, HuT-78 by downregulating constitutive NF-kappaB and thereby Bcl-xl expression.
Pubmed
Journal: Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences
January/9/2013
Abstract
OBJECTIVE
To investigate whether the protection of ischemic preconditioning (IPC) against myocardial ischemia/reperfusion (I/R) injury is mediated by toll-like receptor 4 (TLR4)/NF-κB pathway, and whether these effects are related to the release of calcitonin gene-related peptide (CGRP).
METHODS
Sprague-Dawley rats were subjected to 60 min of ligation of the left anterior descending coronary artery followed by 3 h of reperfusion to induce I/R injury. IPC was performed by 4 cycles of 3-min left coronary artery occlusion followed by 5-min reperfusion before the I/R. The expression of TLR4 mRNA was determined by RT-PCR. TLR4 and NF-κB protein expression were analyzed by immunohistochemistry. Myocardial infarct size, CGRP concentration in plasma and activity of creatine kinase in serum were also measured.
RESULTS
IPC significantly reduced the infarct size and creatine kinase activity concomitantly with the increase in plasma CGRP concentration. The expressions of TLR4 protein and mRNA and NF-κB protein were increased by myocardial I/R injury, and dramatically inhibited by IPC.
CONCLUSIONS
IPC protects against myocardial I/R injury by inhibition of TLR4/NF-κB pathway. These effects are related to the increased the release of CGRP.
Pubmed
Journal: The Journal of nutritional biochemistry
November/1/2012
Abstract
Biphenolic components in the Magnolia family have shown several pharmacological activities such as antitumor effects. This study investigated the effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, on human colon cancer cell growth and its action mechanism. 4-O-methylhonokiol (0-30 μM) decreased constitutive activated nuclear factor (NF)-κB DNA binding activity and inhibited growth of human colon (SW620 and HCT116) cancer cells. It also caused G₀-G₁ phase cell cycle arrest followed by an induction of apoptotic cell death. However, knockdown with small interfering RNA (siRNA) of p21 or transfection with cyclin D1/Cdk4 binding site-mutated p21 abrogated MH-induced cell growth inhibition, inhibition of NF-κB activity as well as expression of cyclin D1 and Cdk4. Conversely, inhibition of NF-κB with specific inhibitor or siRNA augmented MH-induced apoptotic cell death. 4-O-methylhonokiol inhibited tumor growth, NF-κB activity and expression of antiapoptotic proteins; however, it increased the expression of apoptotic proteins as well as p21 in xenograft nude mice bearing SW620 cancer cells. The present study reveals that MH causes p21-mediated human colon cancer cell growth inhibition through suppression of NF-κB and indicates that this compound by itself or in combination with other anticancer agents could be useful for the treatment of cancer.
Pubmed
Journal: Molecular and cellular biochemistry
September/24/2007
Abstract
Small-conductance Ca(2+)-activated K(+) channels (SK) of the SK2 subtype are widely expressed in the central nervous system where they contribute to the control of neuronal excitability. Two SK2 isoforms, SK2-S and SK2-L, the latter representing an N-terminally extended protein of SK2-S, are expressed in similar patterns in the brain. However, our understanding of mechanisms by which the expression of SK2 is regulated is limited. We identified one functional glucocorticoid response element (GRE) at position -2248 bp and two functional nuclear factor-kappB (NF-kappaB) response elements at positions -1652 and -1586 bp in the SK2-S promoter. An increase in SK2-S promoter activity was observed in PC12 cells transiently transfected with a wild-type SK2-S promoter-luciferase reporter gene construct and treated with aldosterone or dexamethasone. The mineralocorticoid receptor (MR) antagonist spironolactone or the glucocorticoid receptor (GR) antagonist mifepristone fully inhibited aldosterone or dexamethasone activation of the SK2-S promoter, respectively. SK2-S promoter activity was also induced by the cell-permeable ceramide analog, N-acetylsphingosine (C2-ceramide). Antisense oligonucleotides directed to NF-kappaB p65 or p50 suppressed SK2-S transcription induced by C2-ceramide. Deletion studies showed that only the -1586 bp NF-kappaB binding site was necessary for maximum C2-ceramide response. Finally, we showed that activation of GRs but not of MRs repressed the NF-kappaB-mediated induction of SK2-S transcription. These findings suggest a possible transcriptional cross talk between GRs and NF-kappaB in the intronic promoter regulation of SK2-S channel gene transcription.
Pubmed
Journal: FEMS immunology and medical microbiology
March/6/2012
Abstract
Pulmonary epithelial cells produce neutrophil chemotactic activity in response to pathogenic bacterial infections, resulting in neutrophil migration to infection sites. Elicited neutrophils in the inflamed tissues were found to be dependent on bradykinin B1 receptor (B1R), which shows high affinity for the active metabolites derived from bradykinin. Thus, the up-regulation of bradykinin and B1R expression represents an important host defense response against invading microbes such as Pseudomonas aeruginosa. However, the effect of P. aeruginosa on the expression of B1R remains unclear, while P. aeruginosa infection is known to stimulate the production of bradykinin. Here, we report that human B1R (hB1R) transcription is up-regulated in host cells co-cultured with P. aeruginosa. Components secreted from P. aeruginosa play a major role in the up-regulation, and the secretion of the components is not controlled by either type III secretion system or quorum sensing. Moreover, the B1R induction is mediated by a NF-κB signaling pathway in human lung epithelial cells. Taken together, this study demonstrates that P. aeruginosa is capable of up-regulating hB1R expression via the NF-κB signaling pathway.
Pubmed
Journal: Pediatric research
September/24/2015
Abstract
BACKGROUND
Hyperoxic reoxygenation following hypoxia increases the expression of inflammatory genes in the neonatal mouse brain. We have therefore compared the temporal profile of 44 a priori selected genes after hypoxia and hyperoxic or normoxic reoxygenation.
METHODS
Postnatal day 7 mice were subjected to 2 h of hypoxia (8% O2) and 30 min reoxygenation with 60% or 21% O2. After 0 to 72 h observation, mRNA and protein were examined in the hippocampus and striatum.
RESULTS
There were significantly higher gene expression changes in six genes after hyperoxic compared to normoxic reoxygenation. Three genes had a generally higher expression throughout the observation period: the inflammatory genes Hmox1 (mean difference: 0.52, 95% confidence interval (CI): 0.15-1.01) and Tgfb1 (mean difference: 0.099, CI: 0.003-0.194), and the transcription factor Nfkb1 (mean difference: 0.049, CI: 0.011-0.087). The inflammatory genes Cxcl10 and Il1b, and the DNA repair gene Neil3, had a higher gene expression change after hyperoxic reoxygenation at one time point only. Nineteen genes involved in inflammation, transcription regulation, apoptosis, angiogenesis, and glucose transport had significantly different gene expression changes with time in all intervention animals.
CONCLUSIONS
We confirm that hyperoxic reoxygenation induces a stronger inflammatory gene response than reoxygenation with air.
Pubmed
Journal: International journal of radiation biology
June/26/2013
Abstract
OBJECTIVE
This study explored the effects of low-dose and low-dose-rate irradiation in human lung fibroblast CCD-18Lu cells and examined the role of AKT (protein kinase B, PKB) in cellular responses.
METHODS
We examined cell survival after chronic low-dose irradiation (0.01 Gy or 0.05 Gy) with challenging high-dose (2 or 10 Gy) irradiation. We examined the effect of AKT activation on cell survival after chronic low-dose radiation using transduced cells with retroviral vector expressing constitutively active AKT (CA-AKT).
RESULTS
Chronic low-dose priming irradiation increased cells viability against the challenging high-dose irradiation. Irradiation at 0.05 Gy increased cellular levels of AKT and acinus long form (L) and short form (S). The chronic low-dose radiation promoted cells proliferation in the exogenously expressed CA-AKT cells. It also increased nuclear factor-kappa B (NF-κB) activity in a biphasic induction pattern. Suppression of NF-κB activation by mutant form of inhibitor of kappa B alpha (IκBαM) antagonized the radiation-induced expression of AKT and acinus L and S.
CONCLUSIONS
Chronic low-dose radiation increases the levels of AKT and acinus proteins via NF-κB activation, and the NF-κB/AKT pathway responding to chronic low-dose irradiation plays an important role in the radiation adaptive response.
Pubmed
Journal: Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases
September/6/2010
Abstract
OBJECTIVE
To explore the effects of nuclear factor kappa B (NF-kappaB) in rabbit immune-complex-induced acute lung injury(ALI).
METHODS
Thirty rabbits were randomly divided into 5 groups, including N, M2h, M4h, M6h and M8h groups. N group was the normal control group. M2h, M4h, M6h and M8h groups were ALI model groups. The rabbits in the N group were treated with intra-tracheal injection of 1 ml normal saline and another dose of normal saline (2 ml/kg) injected via the marginal ear vein. The rabbits in the model groups were injected intra-trachea with bovine serum albumin antibody (anti-BSA)1 ml and injected with bovine serum albumin(BSA) via marginal ear vein at dose of 2 ml/kg. Then the rabbits in the N group were killed at 8 h. The rabbits in M2h, M4h, M6h and M8h groups were killed at 2 h, 4 h, 6 h and 8 h respectively. The maleic dialdehyde (MDA) concentrations, the superoxide dismutase (SOD) activity, the protein concentrations in bronchoalveolar lavage fluid (BALF) and lung wet/dry weight ratio (W/D) were measured. The cellular distribution of NF-kappaB P65 in lung tissues was determined by immunohistochemistry.
RESULTS
The concentrations of MDA, protein in BALF and W/D of lung tissue in M2h, M4h, M6h, M8h groups increased significantly as compared with those in the N group. On the contrary, the activity of SOD in BALF in the model groups decreased significantly as compared with that of the N group. Increased expression of NF-kappaB in inflammatory cells was found in lung tissues from the model groups. The number of positive cells in M2h, M4h, M6h, M8h groups [(26.5 +/- 5.9), (39.9 +/- 6.9), (51.0 +/- 6.3), (58.0 +/- 5.3)] increased significantly as compared with that in the N group [(7.4 +/- 1.9), (t = 8.73 - 25.33, P < 0.01)].
CONCLUSIONS
Immune-complex-induced ALI animal models can be established by intra-tracheal injection of anti-BSA serum and venous injection of BSA. NF-kappaB may play an important role in immune-complex-induced ALI by inflammatory mechanism.
Pubmed
Journal: Scandinavian journal of infectious diseases
May/9/2012
Abstract
BACKGROUND
Crimean-Congo hemorrhagic fever (CCHF) is an acute viral hemorrhagic fever caused by the Crimean-Congo hemorrhagic fever virus (CCHFV). Nuclear factor (NF)-κB regulates the expression of hundreds of genes, including inflammatory and immunoregulatory, cell cycle regulating, and anti-apoptotic genes. NF-κBIA (IκBα) encodes an inhibitory version of the NF-κB proteins.
METHODS
This study is the first to investigate the association between NF-κB1 - 94W/D and NF-κBIA 3→UTR A→G polymorphisms and CCHF using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
RESULTS
There was a significant difference in NF-κB1 - 94W/D genotype distribution between CCHF patients and control populations (p = 0.001). Comparison of the WW genotype with both WD and DD genotypes revealed that the difference between CCHF patients and controls was statistically significant (p = 0.043 for WD genotype, p = 0.018 for DD genotype). However, a significant deviation was found between patients with fatal CCHF and control populations (p = 0.025). The results show that patients with fatal CCHF with the DD genotype have a 4.06-times higher risk for CCHF compared to patients in the control group (odds ratio (OR) 4.06, 95% confidence interval (CI) 1.11-14.87). A significant difference in NF-κBIA 3→UTR A→G polymorphisms was observed between CCHF patients and controls in both AA vs AG and AA vs GG (OR 2.04, p = 0.019; OR 2.01, p = 0.049, respectively).
CONCLUSIONS
Our findings suggest that NF-κB1 - 94W/D and NF-κBIA 3→UTR A→G polymorphisms may be valuable predictors of the clinical course in CCHF disease.
Pubmed
Journal: Journal of cellular physiology
June/28/2009
Abstract
Invasion of tumor cells is the primary cause of therapeutic failure in the treatment of malignant chondrosarcomas. Glial cell-derived neurotrophic factor (GDNF) plays a crucial role in migration and metastasis of human cancer cells. Integrins are the major adhesive molecules in mammalian cells. Here we found that GDNF directed the migration and increased cell surface expression of alphav and beta3 integrin in human chondrosarcoma cells. Pretreated of JJ012 cells with MAPK kinase (MEK) inhibitors PD98059 or U0126 inhibited the GDNF-mediated migration and integrin expression. Stimulation of cells with GDNF increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited GDNF-mediated cells migration and integrin up-regulation. Stimulation of cells with GDNF induced IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the GDNF-mediated increasing of kappaB-luciferase activity was inhibited by PD98059, U0126, PDTC and TPCK or MEK, ERK, IKKalpha, and IKKbeta mutants. Taken together, these results suggest that the GDNF acts through MEK/ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrin and contributing the migration of human chondrosarcoma cells.
Pubmed
Journal: AIDS (London, England)
October/3/1996
Abstract
OBJECTIVE
An enhanced nuclear factor (NF)-kappa B activation in response to tumour necrosis factor (TNF)-alpha has been observed in stably tat-transfected cells. Recent experimental evidence suggests that Tat may autocrinously influence both cellular physiology and HIV-1 long terminal repeat-directed gene expression in Tat-producing cells. Therefore, the possible association of a Tat autocrinous loop with the enhanced NF-kappa B-binding activity induced by TNF-alpha in Tat-producing cells was studied by anti-Tat antibody blocking experiments.
METHODS
Permanently tat-transfected Jurkat cells, maintained either in the presence or absence of anti-Tat antibody, were studied for the presence of TNF-alpha-induced NF-kappa B-binding activity (quantified by electrophoretic mobility shift assays) and the presence of cell-surface-bound Tat (determined by flow cytometry and confocal microscopy of anti-Tat immunofluorescence-stained cell preparations.
RESULTS
The enhanced production of TNF-alpha-induced NF-kappa B binding activity exhibited by tat-transfected Jurkat cells was completely abolished in cell cultures maintained in the presence of anti-Tat antibody, thus indicating that the increased TNF-alpha-induced NF-kappa B binding activity observed in Jurkat-tat cells was dependent on the presence of Tat protein in an antibody-accessible location. In accordance with these findings, immunofluorescence-stained preparations of unfixed tat-transfected Jurkat cells showed the presence of cell-surface-bound Tat protein which was completely absent in cells incubated in the presence of anti-Tat antibodies.
CONCLUSIONS
This study demonstrates that the enhanced NF-kappa B activation exhibited by stably tat-transfected cells in response to TNF-alpha, is associated with cell surface interaction of extracellularly released Tat protein. These data add further evidence to the possible relevance of a Tat autocrinous loop in the physiology of Tat-producing cells and suggest that in HIV-1-infected cells Tat is likely to behave as a bifunctional molecule which not only acts from within facilitating NF-kappa B recruitment in the viral transcription complex, but may also act from without increasing the availability of activated NF-kappa B.
Pubmed
Journal: Neurological research
January/16/2017
Abstract
OBJECTIVE
This study aims to investigate gene expression changes in rat dorsal horns after sciatic nerve injury (SNI).
METHODS
The GSE18803 microarray data collected from young and adult rats were downloaded from GEO. After preprocessing, differentially expressed genes (DEGs) between SNI and sham-operated groups were selected using Limma package, in young and adult group, respectively, followed by Venn analysis. Then, enrichment analyses were performed for these DEGs using DAVID. The STRING database was used to identify protein-protein interactions (PPIs) among these DEGs, and the module network was further extracted using plugin ClusterONE. Finally, protein domain enrichment analysis of DEGs in each module was performed using InterPro database.
RESULTS
Totally, 210 and 50 DEGs were identified in adult and young group, respectively. Among them, 160 were specific in adult group (e.g. CCL2, NF-κB1 and RAC2); 9 were specific in young group (e.g. ILF3 and LYVE1); and 41 were common in both two groups (e.g. FCER1G, C1QA, C1QB and C1QC). The up-regulated DEGs were mostly enriched in immune response-related biological processes, as well as 15 immune- and inflammation-related pathways. Then, two modules were identified in PPI network. CCL2 and NF-κB1 had high connectivity degrees in module 1, and RAC2, FCER1G and CD68 in module 2.
CONCLUSIONS
CCL2, NF-κB1, RAC2, FCER1G and C1Q may contribute to the generation of neuropathic pain after SNI via immune and defense pathways. Among the five genes, the first three are specific in adult population, while the latter two are age-independent. They all might function through involvement of these immune or inflammatory pathways.
Pubmed
Journal: Virus research
October/22/2015
Abstract
Dengue virus (DENV) infection associates with renal disorders. Patients with dengue hemorrhagic fever and acute kidney injury have a high mortality rate. Increased levels of cytokines may contribute to the pathogenesis of DENV-induced kidney injury. Currently, molecular mechanisms how DENV induces kidney cell injury has not been thoroughly investigated. Excessive cytokine production may be involved in this process. Using human cytokine RT(2) Profiler PCR array, 14 genes including IP-10, RANTES, IL-8, CXCL-9 and MIP-1β were up-regulated more than 2 folds in DENV-infected HEK 293 cells compared to that of mock-infected HEK 293 cells. In the present study, RANTES was suppressed by the NF-κB inhibitor, compound A (CpdA), in DENV-infected HEK 293 cells implying the role of NF-κB in RANTES expression. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB binds more efficiently to its binding sites on the RANTES promoter in NS5-transfected HEK 293 cells than in HEK 293 cells expressing the vector lacking NS5 gene. To further examine whether the NS5-activated RANTES promoter is mediated through NF-κB, the two NF-κB binding sites on the RANTES promoter were mutated and this promoter was coupled to the luciferase cDNA. The result showed that when both binding sites of NF-κB in the RANTES promoter were mutated, the ability of NS5 to induce the luciferase activity was significantly decreased. Therefore, DENV NS5 activates RANTES production by increasing NF-κB binding to its binding sites on the RANTES promoter.
Pubmed
Journal: Proceedings of the National Academy of Sciences of the United States of America
June/15/1994
Abstract
The gene encoding the 105-kDa protein (p105) precursor of the p50 subunit of transcription factor NF-kappa B also encodes a p70 I kappa B protein, I kappa B gamma, which is identical to the C-terminal 607 amino acids of p105. Here we show that alternative RNA splicing generates I kappa B gamma isoforms with properties different from those of p70. One 63-kDa isoform, termed I kappa B gamma-1, which lacks 59 amino acids C-terminal to ankyrin repeat 7, has a novel 35-amino acid C terminus encoded by an alternative reading frame of the p105 gene. A 55-kDa isoform, I kappa B gamma-2, lacks the 190 C-terminal amino acids of p70I kappa B gamma. In contrast to p70I kappa B gamma, which is a cytoplasmic protein, I kappa B gamma-1 is found in both the cytoplasm and nucleus, whereas I kappa B gamma-2 is predominantly nuclear. The I kappa B gamma isoforms also display differences in specificity and affinity for Rel/NF-kappa B proteins. While p70I kappa B gamma inhibits p50-, p65-, and c-Rel-mediated transactivation and/or DNA binding, both I kappa B gamma-1 and I kappa B gamma-2 are specific for p50 and have different affinities for this subunit. The absence in I kappa B gamma-1 and I kappa B gamma-2 of a protein kinase A site whose phosphorylation modulates p70I kappa B gamma inhibitory activity suggests that alternative RNA splicing may be used to generate I kappa B gamma isoforms that respond differently to intracellular signals.
Pubmed
Journal: Microbes and infection
January/25/2009
Abstract
Borrelia burgdorferi invasion of mammalian joints results in genesis of Lyme arthritis. Other than spirochete lipids, existence of protein antigens, which are abundant in joints and participate in B. burgdorferi-induced host inflammatory response, is unknown. Here, we report that major products of the B. burgdorferi basic membrane protein (bmp) A/B operon that are induced in murine and human joints, possess inflammatory properties. Compared to the wild type B. burgdorferi, an isogenic bmpA/B mutant induced significantly lower levels of pro-inflammatory cytokines TNF-alpha and IL-1beta in cultured human synovial cells, which could be restored using bmpA/B-complemented mutants, and more directly, upon addition of recombinant BmpA, but not BmpB or control spirochete proteins. Non-lipidated and lipidated versions of BmpA induced similar levels of cytokines, and remained unaffected by treatment with lipopolysaccharide inhibitor, polymyxin B. The bmpA/B mutant was also impaired in the induction of NF-kappaB and p38 MAP kinase signaling pathways in synovial cells, which were activated by non-lipidated BmpA. These results show that a protein moiety of BmpA can induce cytokine responses in synovial cells via activation of the NF-kappaB and p38 MAP kinase pathways and thus, could potentially contribute to the genesis of Lyme arthritis.
Pubmed
Journal: Journal of cancer research and clinical oncology
March/31/2013
Abstract
OBJECTIVE
In our previous publication, we have shown that dihydroartemisinin could significantly inhibit the growth of CML K562 cells by its anti-proliferative and inducing apoptotic effects. Given the pivotal effect of Bcr/Abl tyrosine kinase and its downstream signal factors on CML cell proliferation and survival, we extend our study to investigate the effect of DHA on Bcr/Abl and related signal factors to further illuminate the possible mechanisms of the effect of DHA on CML cells.
METHODS
The expression of Bcr/Abl was analyzed with PCR and Western blotting methods at both mRNA and protein levels. Measurement of protein expression and tyrosine phosphorylation activity of Bcr/Abl, AKT, ERK1/2, NF-κB and cytochrome c were performed with Western blotting and immunoprecipitation methods. Using the activity kits analyzed the activity of caspase 9 and caspase 3.
RESULTS
The treatment with DHA results in a significant suppression on Bcr/Abl expression and leads to a concentration-dependent reduction on the Bcr/Abl tyrosine activity. Moreover, it also results in a strong influence on the downstream signal factors of Bcr/Abl, which includes inhibition of tyrosine kinase activity of AKT and ERK1/2, suppression of NF-κB protein expression, promotion of the cytochrome c release and the consequential activation of caspase 3/9 in CML K562 cells.
CONCLUSIONS
Together with our previous report, our data show that the growth inhibitory effect of DHA on CML cells might be due to the influence on Bcr/Abl expression and its downstream signal factors. DHA might be a potential novel anti-CML drug candidate and worthy of further study.
Pubmed
Journal: Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
September/30/2012
Abstract
OBJECTIVE
To study the expression and effect of TLR4 and NFkappaB protein in hippocampus neuron in rats exposed to chronic hypoxic hypercapnia.
METHODS
The disorder of learning-memory in pulmonary hypertension rat model was reproduced by chronic hypoxic hypercapnia. Thirty rats were randomly divided into three groups: normal control group, hypoxic hypercapnia 2-week and 4-week group. The number of apoptosis neurons in hippocampus CA1/3 was counted by TUNEL method. Activity of TLR4 and NFkappaB in hippocampus CA1/3 was detected by using SP immunocytochemical technique.
RESULTS
The expression of TLR4 protein in hippocampus CA1/3 in group 2HH( CA1: 0.1275 +/- 0.0242, CA3: 0.1156 +/- 0.0376) and 4HH (CA1: 0.1522 +/- 0.0187, CA3: 0.1427 +/- 0.0453) were significantly higher than those in the NC group (P < 0.05, P < 0.01). The positive expression of NFkappaB were showed in cell nucleus in group 2HH (CA1: 0.1326 +/- 0.0324, CA3: 0.1301 +/- 0.0112) and group 4HH (CA1: 0.1612 +/- 0.0428, CA3: 0.1578 +/- 0.0365), and significantly higher than those in the NC group (P < 0.05, P < 0.01). The apoptosis of neural cells in hippocampus CA1/3 gradually increased with the time of exposure, and reached peak at 4 weeks (P < 0.01 vs NC group).
CONCLUSIONS
The activation of TLR4 and NFkappaB may play an important role in the apoptosis of hippocampus neural cells in rat exposed to chronic hypoxic hypercapnia.
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