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PAFR activation of NF-κB p65 or p105 precursor dictates pro- and anti-inflammatory responses during TLR activation in murine macrophages.
Ishizuka EK, Filgueiras LR, Rios FJ, Serezani CH, Jancar S
(2016) Sci Rep 6: 32092
MeSH Terms: Animals, Cytokines, Inflammation, Inflammation Mediators, Interleukin-10, Lipopolysaccharides, Lipoproteins, Macrophages, Peritoneal, Male, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, NF-kappa B p50 Subunit, Platelet Activating Factor, Platelet Membrane Glycoproteins, Receptors, G-Protein-Coupled, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptors, Transcription Factor RelA
Show Abstract · Added May 4, 2017
Platelet-activating factor receptor (PAFR) is a G protein-coupled receptor (GPCR) implicated in many diseases. Toll-like receptors (TLRs) play a critical role in shaping innate and adaptive immune responses. In this study, we investigated whether PAFR signaling changes the macrophages responsiveness to agonists of TLR2 (Pam3Cys), TLR4 (LPS), and TLR3 agonist Poly(I:C). Exogenous PAF inhibited the production of pro-inflammatory cytokines (IL-12p40, IL-6, and TNF-α) and increased anti-inflammatory IL-10 in macrophages challenged with Pam3Cys and LPS, but not with Poly (I:C). PAF did not affect mRNA expression of MyD88, suggesting that PAF acts downstream the adaptor. PAF inhibited LPS-induced phosphorylation of NF-κB p65 and increased NF-κB p105 phosphorylation, which is processed in the proteasome to generate p50 subunit. The PAF potentiation of IL-10 production was dependent on proteasome processing but independent of NF-κB transactivation domain. Inhibition of p50 abolished the PAF-induced IL-10 production. These findings indicate that the impaired transcriptional activity of the p65 subunit and the enhanced p105 phosphorylation induced by PAF are responsible for down regulation of pro-inflammatory cytokines and up regulation of IL-10, respectively, in LPS-challenged macrophages. Together, our data unveil a heretofore unrecognized role for PAFR in modulating activation of NF-κB in macrophages.
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19 MeSH Terms
NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis.
Brown JD, Lin CY, Duan Q, Griffin G, Federation A, Paranal RM, Bair S, Newton G, Lichtman A, Kung A, Yang T, Wang H, Luscinskas FW, Croce K, Bradner JE, Plutzky J
(2014) Mol Cell 56: 219-231
MeSH Terms: Acetylation, Animals, Atherosclerosis, Azepines, Cell Adhesion, Cell Movement, Cells, Cultured, Chromatin, E-Selectin, Endothelial Cells, Endothelium, Vascular, Enhancer Elements, Genetic, Histones, Humans, Inflammation, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B p50 Subunit, Nuclear Proteins, Protein Binding, RNA Polymerase II, Regulatory Sequences, Nucleic Acid, SOXF Transcription Factors, Signal Transduction, Transcription Factor RelA, Transcription Factors, Transcription Initiation, Genetic, Transcription, Genetic, Triazoles, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1
Show Abstract · Added September 6, 2016
Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
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33 MeSH Terms
Genetic polymorphism of NFKB1 and NFKBIA genes and liver cancer risk: a nested case-control study in Shanghai, China.
Gao J, Xu HL, Gao S, Zhang W, Tan YT, Rothman N, Purdue M, Gao YT, Zheng W, Shu XO, Xiang YB
(2014) BMJ Open 4: e004427
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Case-Control Studies, China, Female, Genetic Predisposition to Disease, Haplotypes, Humans, I-kappa B Proteins, Liver Neoplasms, Male, Middle Aged, NF-KappaB Inhibitor alpha, NF-kappa B p50 Subunit, Polymorphism, Single Nucleotide
Show Abstract · Added March 10, 2014
OBJECTIVES - Genetic variations of nuclear factor-κB (NF-κB) signalling pathway were found to be associated with inflammatory diseases and several malignancies. However, little is known about NF-κB pathway gene polymorphisms and susceptibility of liver cancer. The aim of this study was to investigate whether genetic variants of NFKB1 and NFKBIA were associated with risk of liver cancer in a Chinese population.
DESIGN - The study was designed as a nested case-control study within two prospective cohorts (the Shanghai Women's Health Study, SWHS, 1996-2000 and the Shanghai Men's Health Study, SMHS, 2002-2006).
SETTINGS - This population-based study was conducted in urban Shanghai, China.
PARTICIPANTS - A total of 217 incident liver cancer cases diagnosed through 31 December 2009 and 427 healthy controls matched by sex, age at baseline (±2 years) and date (±30 days) of sample collection were included in the study.
PRIMARY AND SECONDARY OUTCOME MEASURES - Genetic polymorphisms of NFKB1 and NFKBIA were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. OR and its 95% CIs were estimated by an unconditional logistic regression model to measure the association between selected SNPs and the risk of liver cancer.
RESULTS - After adjusted for potential confounding factors, rs28362491 ins/del or del/del genotypes were associated with higher risk of liver cancer with an adjusted OR 1.54 (95% CI 1.04 to 2.28). rs230496 AG and GG genotypes were also noted with higher risk of liver cancer with an adjusted OR 1.53 (95% CI 1.03 to 2.26). Haplotype analysis indicated that carriers of the NFKB1 GA and AA (rs230525-rs230530) haplotypes had higher risk of liver cancer under an additive model. No association was observed between NFKBIA variants and risk of live cancer.
CONCLUSIONS - Our results suggest that genetic variants of NFKB1 influence liver cancer susceptibility in Chinese population, although replication in other studies is needed.
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16 MeSH Terms
Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase α-subunit gene expression by miRNA.
Zhang YM, Noto JM, Hammond CE, Barth JL, Argraves WS, Backert S, Peek RM, Smolka AJ
(2014) Am J Physiol Gastrointest Liver Physiol 306: G606-13
MeSH Terms: 3' Untranslated Regions, Achlorhydria, Antigens, Bacterial, Bacterial Proteins, Binding Sites, Cell Line, Gastric Mucosa, Gene Expression Regulation, Enzymologic, Genes, Reporter, H(+)-K(+)-Exchanging ATPase, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, MicroRNAs, NF-kappa B p50 Subunit, Parietal Cells, Gastric, Peptidoglycan, RNA Interference, RNA Processing, Post-Transcriptional, RNA, Messenger, Time Factors, Transfection, Virulence
Show Abstract · Added March 10, 2014
Acute Helicobacter pylori infection of gastric epithelial cells induces CagA oncoprotein- and peptidoglycan (SLT)-dependent mobilization of NF-κB p50 homodimers that bind to H-K-ATPase α-subunit (HKα) promoter and repress HKα gene transcription. This process may facilitate gastric H. pylori colonization by induction of transient hypochlorhydria. We hypothesized that H. pylori also regulates HKα expression posttranscriptionally by miRNA interaction with HKα mRNA. In silico analysis of the HKα 3' untranslated region (UTR) identified miR-1289 as a highly conserved putative HKα-regulatory miRNA. H. pylori infection of AGS cells transfected with HKα 3' UTR-Luc reporter construct repressed luciferase activity by 70%, whereas ΔcagA or Δslt H. pylori infections partially abrogated repression. Transfection of AGS cells expressing HKα 3' UTR-Luc construct with an oligoribonucleotide mimetic of miR-1289 induced maximal repression (54%) of UTR activity within 30 min; UTR activity was unchanged by nontargeting siRNA transfection. Gastric biopsies from patients infected with cagA(+) H. pylori showed a significant increase in miR-1289 expression compared with uninfected patients or those infected with cagA(-) H. pylori. Finally, miR-1289 expression was necessary and sufficient to attenuate biopsy HKα protein expression in the absence of infection. Taken together, these data indicate that miR-1289 is upregulated by H. pylori in a CagA- and SLT-dependent manner and targets HKα 3' UTR, affecting HKα mRNA translation. The sensitivity of HKα mRNA 3' UTR to binding of miR-1289 identifies a novel regulatory mechanism of gastric acid secretion and offers new insights into mechanisms underlying transient H. pylori-induced hypochlorhydria.
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24 MeSH Terms
Targeting nuclear import shuttles, importins/karyopherins alpha by a peptide mimicking the NFκB1/p50 nuclear localization sequence.
Zienkiewicz J, Armitage A, Hawiger J
(2013) J Am Heart Assoc 2: e000386
MeSH Terms: Active Transport, Cell Nucleus, Cell Nucleus, Cell-Penetrating Peptides, Cells, Cultured, Humans, NF-kappa B p50 Subunit, Nuclear Localization Signals, alpha Karyopherins
Show Abstract · Added March 27, 2014
BACKGROUND - We recently reported that a bifunctional nuclear transport modifier (NTM), cSN50.1 peptide, reduced atherosclerosis, plasma cholesterol, triglycerides, and glucose along with liver fat and inflammatory markers, in a murine model of familial hypercholesterolemia. We determined that cSN50.1 improved lipid homeostasis by modulating nuclear transport of sterol regulatory element-binding proteins through interaction with importin β. Previous studies established that cSN50.1 and related NTMs also modulate nuclear transport of proinflammatory transcription factors mediated by binding of their nuclear localization sequences (NLSs) to importins/karyopherins α. However, selectivity and specificity of NTMs for importins/karyopherins α were undetermined.
METHODS AND RESULTS - We analyzed interaction of the NTM hydrophilic module, N50 peptide, derived from the NLS of NFκB1/p50, with endogenous human importins/karyopherins α to determine the mechanism of NTM modulation of importin α-mediated nuclear transport. We show that N50 peptide forms stable complexes with multiple importins/karyopherins α. However, only interaction with importin α5 (Imp α5) displayed specific, high-affinity binding. The 2:1 stoichiometry of the N50-Imp α5 interaction (KD1 = 73 nmol/L, KD2 = 140 nmol/L) indicated occupancy of both major and minor NLS binding pockets. Utilizing in silico 3-dimensional (3-D) docking models and comparative structural analysis, we identified a structural component of the Imp α5 major NLS binding pocket that may stabilize N50 binding. Imp α5 also displayed rapid stimulus-induced turnover, which could influence its availability for nuclear transport during the inflammatory response.
CONCLUSIONS - These results provide direct evidence that N50 peptide selectively targets Imp α5, encouraging further refinement of NLS-derived peptides as new tools to modulate inflammatory disorders.
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8 MeSH Terms
Inactivation of NF-kappaB p50 leads to insulin sensitization in liver through post-translational inhibition of p70S6K.
Gao Z, Yin J, Zhang J, He Q, McGuinness OP, Ye J
(2009) J Biol Chem 284: 18368-76
MeSH Terms: Animals, Body Weight, Carrier Proteins, Cells, Cultured, Dietary Fats, Female, Fibroblasts, Glucose Clamp Technique, Hepatocytes, Hyperinsulinism, I-kappa B Kinase, Insulin Resistance, Liver, Male, Mice, Mice, Inbred Strains, Mice, Knockout, NF-kappa B p50 Subunit, Obesity, Phosphotransferases (Alcohol Group Acceptor), Protein Processing, Post-Translational, Ribosomal Protein S6 Kinases, 70-kDa, TOR Serine-Threonine Kinases, Tumor Necrosis Factor-alpha
Show Abstract · Added July 21, 2014
In this study, we investigated the metabolic phenotype of the NF-kappaB p50 knock-out (p50-KO) mice. Compared with wild type mice, the p50-KO mice had an increase in food intake, but a decrease in body fat content. On chow diet, their blood glucose dropped much more than the wild type (WT) mice in the insulin tolerance test. Their glucose infusion rate was 30% higher than that of the WT mice in the hyperinsulinemic-euglycemic clamp. Their hepatic glucose production was suppressed more actively by insulin, and their insulin-induced glucose uptake was not altered in skeletal muscle or adipose tissue. In the liver, their p70S6K (S6K1) protein was significantly lower, and tumor necrosis factor-alpha (TNF-alpha) expression was much higher. Their S6K1 protein was reduced by TNF-alpha treatment in the primary culture of hepatocytes. S6K1 reduction was blocked by the proteasome inhibitor MG132. In their livers, IKK2 (IKKbeta) activity was reduced together with IKKgamma. Their S6K1 degradation was dependent on IKK2 deficiency. Reconstitution of the S6K1 protein in their liver blocked the increase in insulin sensitivity. S6K1 degradation was not observed in hepatocytes of the WT mice. The data suggest that inactivation of NF-kappaB p50 leads to suppression of IKK2 activity in the liver. IKK2 deficiency leads to S6K1 inhibition through TNF-induced protein degradation. The S6K1 reduction may contribute to insulin sensitivity in p50-KO mice. This study suggests that hepatic S6K1 may be a drug target in the treatment of insulin resistance.
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24 MeSH Terms
Myeloid cells control termination of lung inflammation through the NF-kappaB pathway.
Han W, Joo M, Everhart MB, Christman JW, Yull FE, Blackwell TS
(2009) Am J Physiol Lung Cell Mol Physiol 296: L320-7
MeSH Terms: Animals, Cell Line, Chemokines, CXC, Coculture Techniques, Female, Humans, I-kappa B Proteins, Lipopolysaccharides, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myeloid Cells, NF-KappaB Inhibitor alpha, NF-kappa B, NF-kappa B p50 Subunit, Neutrophils, Pneumonia, Transplantation Chimera
Show Abstract · Added February 26, 2013
Although acute lung inflammation in response to local or systemic infection involves myeloid and nonmyeloid cells, the interplay between different cell types remains poorly defined. Since NF-kappaB is a key transcription factor for innate immunity, we investigated whether dysregulated NF-kappaB activation in myeloid cells impacts inflammatory signaling in nonmyeloid cells and generation of neutrophilic lung inflammation in response to systemic endotoxemia. We generated bone marrow chimeras by fetal liver transplantation of cells deficient in IkappaBalpha or p50 into lethally irradiated NF-kappaB reporter transgenic mice. No differences were apparent between bone marrow chimeras in the absence of an inflammatory stimulus; however, following intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS), IkappaBalpha- or p50-deficient bone marrow chimeras showed increased NF-kappaB activation in nonhematopoietic cells, exaggerated neutrophilic inflammation, and higher mortality compared with untransplanted reporter mice and wild-type bone marrow chimeras. Primary bone marrow-derived macrophages (BMDM) from IkappaBalpha(-/-) or p50(-/-) exhibited increased NF-kappaB activation and macrophage inflammatory protein-2 production after LPS treatment compared with wild-type cells, and coculture of BMDM with lung epithelial (A549) cells resulted in increased NF-kappaB activation in A549 cells and excess IL-8 production by these epithelial cells. These studies indicate an important role for inhibitory members of the NF-kappaB family acting specifically within myeloid cells to limit inflammatory responses in the lungs.
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21 MeSH Terms
The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to Citrobacter rodentium in colonic epithelial cells by preventing NF-kappaB activation.
Singh K, Chaturvedi R, Asim M, Barry DP, Lewis ND, Vitek MP, Wilson KT
(2008) J Biol Chem 283: 16752-61
MeSH Terms: Animals, Apolipoproteins E, Citrobacter rodentium, Colon, Dose-Response Relationship, Drug, Epithelial Cells, Escherichia coli, I-kappa B Kinase, Inflammation, Mice, Models, Biological, NF-kappa B, NF-kappa B p50 Subunit, Nitric Oxide Synthase Type II, Peptides
Show Abstract · Added March 5, 2014
Inflammatory bowel disease arises from the interplay between luminal bacteria and the colonic mucosa. Targeted inhibition of pro-inflammatory pathways without global immunosuppression is highly desirable. Apolipoprotein (apo) E has immunomodulatory effects and synthetically derived apoE-mimetic peptides are beneficial in models of sepsis and neuroinflammation. Citrobacter rodentium is the rodent equivalent of enteropathogenic Escherichia coli, and it causes colitis in mice by colonizing the surface of colonic epithelial cells and inducing signaling events. We have reported that mice deficient in inducible nitric-oxide (NO) synthase (iNOS) have attenuated C. rodentium-induced colitis. We used young adult mouse colon (YAMC) cells that mimic primary colonic epithelial cells to study effects of an antennapedia-linked apoE-mimetic peptide, COG112, on C. rodentium-activated cells. COG112 significantly attenuated induction of NO production, and iNOS mRNA and protein expression, in a concentration-dependent manner. COG112 inhibited the C. rodentium-stimulated induction of iNOS and the CXC chemokines KC and MIP-2 to the same degree as the NF-kappaB inhibitors MG132 or BAY 11-7082, and there was no additive effect when COG112 and these inhibitors were combined. COG112 significantly reduced nuclear translocation of NF-kappaB, when assessed by electromobility shift assay, immunoblotting, and immunofluorescence for p65. This correlated with inhibition of both C. rodentium-stimulated IkappaB-alpha phosphorylation and degradation, and IkappaB kinase activity, which occurred by inhibition of IkappaB kinase complex formation rather than by a direct effect on the enzyme itself. These studies indicate that apoE-mimetic peptides may have novel therapeutic potential by inhibiting NF-kappaB-driven proinflammatory epithelial responses to pathogenic colonic bacteria.
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15 MeSH Terms
DNA mimicry by a high-affinity anti-NF-kappaB RNA aptamer.
Reiter NJ, Maher LJ, Butcher SE
(2008) Nucleic Acids Res 36: 1227-36
MeSH Terms: Aptamers, Nucleotide, Binding Sites, Models, Molecular, Molecular Mimicry, NF-kappa B, NF-kappa B p50 Subunit, Nuclear Magnetic Resonance, Biomolecular
Show Abstract · Added January 28, 2014
The binding of RNA molecules to proteins or other ligands can require extensive RNA folding to create an induced fit. Understanding the generality of this principle involves comparing structures of RNA before and after complex formation. Here we report the NMR solution structure of a 29-nt RNA aptamer whose crystal structure had previously been determined in complex with its transcription factor target, the p50(2) form of NF-kappaB. The RNA aptamer internal loop structure has pre-organized features that are also found in the complex, including non-canonical base pairing and cross-strand base stacking. Remarkably, the free RNA aptamer structure possesses a major groove that more closely resembles B-form DNA than RNA. Upon protein binding, changes in RNA structure include the kinking of the internal loop and distortion of the terminal tetraloop. Thus, complex formation involves both pre-formed and induced fit binding interactions. The high affinity of the NF-kappaB transcription factor for this RNA aptamer may largely be due to the structural pre-organization of the RNA that results in its ability to mimic DNA.
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7 MeSH Terms
The role of NF-{kappa}B-1 and NF-{kappa}B-2-mediated resistance to apoptosis in lymphomas.
Bernal-Mizrachi L, Lovly CM, Ratner L
(2006) Proc Natl Acad Sci U S A 103: 9220-5
MeSH Terms: Adenoviridae, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Cell Line, Tumor, Humans, I-kappa B Proteins, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Lymphoma, NF-KappaB Inhibitor alpha, NF-kappa B p50 Subunit, Protein Isoforms, RNA, Small Interfering, Signal Transduction, bcl-X Protein
Show Abstract · Added March 5, 2014
The NF-kappaB pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-kappaB pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-kappaB were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-kappaB target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-kappaB pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-kappaB (IkappaB) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-kappaB pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.
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15 MeSH Terms