Phosphorylation of SIMPL modulates RelA-associated NF-κB-dependent transcription

2007 ◽  
Vol 292 (3) ◽  
pp. C1013-C1023 ◽  
Author(s):  
Yong Luo ◽  
Hyung-Joo Kwon ◽  
Sherwin Montano ◽  
Millie Georgiadis ◽  
Mark G. Goebl ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Nuclear Localization ◽  
Critical Role ◽  
Epidemiological Data ◽  
Dependent Manner ◽  
Transactivation Activity ◽  
Tnf Α ◽  
Chronic Activation ◽  
Factor Α ◽  
Necrosis Factor

Epidemiological data have implicated perturbations in the regulation of NF-κB activity to diseases that affect a large number of Americans today. Specifically, chronic activation of genes involved in the inflammatory response is associated with the progression of and complications in diabetes, arthritis, atherosclerosis, and cancer. Insight into the mechanisms governing the regulation of NF-κB transcriptional activity will provide the molecular link between NF-κB and these pathological states. SIMPL (signaling molecule that associates with mouse Pelle-like kinase) is a component of a signaling pathway through which tumor necrosis factor-α (TNF-α) induces NF-κB-controlled gene transcription. SIMPL interacts with the nuclear pool of the NF-κB subunit, p65, in a TNF-α-dependent manner to enhance p65-dependent gene transcription. How SIMPL activity is regulated is unknown. Under basal as well as TNF-α-stimulated conditions, SIMPL phosphopeptides were identified. SIMPL mutants lacking sites that are phosphorylated under basal conditions diminished p65 transactivation activity but had no effect on SIMPL nuclear localization. SIMPL mutants lacking sites of TNF-α-enhanced phosphorylation impaired nuclear localization and prevented TNF-α-induced p65 transactivation activity. Together, these studies reveal that phosphorylation of the SIMPL protein plays a critical role in SIMPL regulation by affecting both SIMPL subcellular localization and the p65 coactivator function of SIMPL.

Epigallocatechin Gallate Modulates Cytokine Production by Bone Marrow-Derived Dendritic Cells Stimulated with Lipopolysaccharide or Muramyldipeptide, or Infected with Legionella pneumophila

2005 ◽  
Vol 230 (9) ◽  
pp. 645-651 ◽  
Author(s):  
James Rogers ◽  
Izabella Perkins ◽  
Alberto van Olphen ◽  
Nicholas Burdash ◽  
Thomas W. Klein ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Tumor Necrosis ◽  
Epigallocatechin Gallate ◽  
Dependent Manner ◽  
Enhanced Production ◽  
Tnf Α ◽  
Factor Α ◽  
Dose Dependent ◽  
Antimicrobial Immunity ◽  
Necrosis Factor

The primary polyphenol in green tea extract is the catechin epigallocatechin gallate (EGCG). Various studies have shown significant suppressive effects of catechin on mammalian cells, either tumor or normal cells, including lymphoid cells. Previous studies from this laboratory reported that EGCG has marked suppressive activity on murine macrophages infected with the intracellular bacterium Legionella pneumophila (Lp), an effect mediated by enhanced production of both tumor necrosis factor-α (TNF-α) and γ-interferon (IFN-γ). In the present study, primary murine bone marrow (BM)-derived dendritic cells (DCs), a phagocytic monocytic cell essential for innate immunity to intracellular microorganisms, such as Lp, were stimulated in vitro with the microbial stimulant lipopolysaccharide (LPS) from gram-negative bacteria, the cell wall component from gram-positive bacteria muramyldipeptide (MDP) or infected with Lp. Production of the T helper cell (Th1)-activating cytokine, interleukin-12 (IL-12) and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α), produced mainly by phagocytic cells and important for antimicrobial immunity, was determined in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Treatment of the cells with EGCG inhibited, in a dose-dependent manner, production of IL-12. In contrast, enhanced production of TNF-α occurred in a dose-dependent manner in the DC cultures stimulated with either soluble bacterial product or infected with Lp. Thus, the results of this study show that the EGCG catechin has a marked effect in modulating production of these immunoregulatory cytokines in stimulated DCs, which are important for antimicrobial immunity, especially innate immunity. Further studies are necessary to characterize the physiologic function of the effect of EGCG on TNF-α and IL-12 during Lp infection, and the mechanisms involved.

Post-transcriptional effects of extracellular pH on tumour necrosis factor-α production in RAW 246.7 and J774 A.1 cells

2001 ◽  
Vol 100 (3) ◽  
pp. 259-266 ◽  
Author(s):  
Thomas A. HEMING ◽  
Divina M. TUAZON ◽  
Sanat K. DAVÉ ◽  
Ashok K. CHOPRA ◽  
Johnny W. PETERSON ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Cell Lines ◽  
Gene Transcription ◽  
Tumour Necrosis ◽  
Extracellular Ph ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
J774 Cells ◽  
Factor Α ◽  
Necrosis Factor

The present studies determined the effects of extracellular pH (pHo) on the production of tumour necrosis factor-α (TNF-α) in the macrophage-like cell lines RAW 246.7 and J774 A.1. The cells were activated with lipopolysaccharide (LPS) at pHo 5.5, 6.5 or 7.4. TNF-α gene transcription was monitored by Northern blot analysis. Synthesis of the cytokine was monitored by ELISA measurements of the TNF-α content of cell-conditioned media (extracellularly released TNF-α) and cell lysates (cytosolic TNF-α). The magnitude of the TNF-α response differed markedly between the two cell lines. RAW cells were more responsive to LPS than were J774 cells. However, the effects of pHo on TNF-α production were similar in the two cell lines. TNF-α gene transcription was insensitive to experimental pHo. The pHo had no effect on the abundance of TNF-α mRNA at 2, 4 or 18 h. Nonetheless, synthesis of TNF-α was affected significantly by pHo. The TNF-α contents of cell-conditioned medium and cell lysate at 18 h were reduced progressively at lower pHo values. The data indicate that pHo alters TNF-α production in RAW and J774 cells at a post-transcriptional level. These findings suggest that pHo influences the phenotypic responses of macrophages to activating stimuli and modifies the role that macrophages play in inflammatory and immune actions.

scholarly journals Extracts of Thai Perilla frutescens nutlets attenuate tumour necrosis factor-α-activated generation of microparticles, ICAM-1 and IL-6 in human endothelial cells

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Narisara Paradee ◽  
Niramon Utama-ang ◽  
Chairat Uthaipibull ◽  
John B. Porter ◽  
Maciej W. Garbowski ◽  
...  
Keyword(s):  
Tumour Necrosis ◽  
Endothelial Activation ◽  
Perilla Frutescens ◽  
Dependent Manner ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Ea.Hy926 Cells ◽  
Factor Α ◽  
Dose Dependent ◽  
Necrosis Factor

Abstract Elevation of endothelial microparticles (EMPs) play an important role in the progression of inflammation-related vascular diseases such as cardiovascular diseases (CVDs). Thai perilla (Perilla frutescens) nutlets are rich in phenolic compounds and flavonoids that exert potent antioxidant and anti-inflammatory effects. We found that the ethyl acetate (EA) and ethanol (Eth) extracts of Thai perilla nutlets contain phenolic compounds such as luteolin, apigenin, chryseoriol and their glycosides, which exhibit antioxidant activity. The goal of the present study was to investigate the effects of the extracts on endothelial activation and EMPs generation in tumour necrosis factor-α (TNF-α)-induced EA.hy926 cells. We found that TNF-α (10 ng/ml) activated EA.hy926 cells and subsequently generated EMPs. Pre-treatment with the extracts significantly attenuated endothelial activation by decreasing the expression of the intracellular adhesion molecule-1 (ICAM-1) in a dose-dependent manner. Only the Eth extract showed protective effects against overproduction of interleukin-6 (IL-6) in the activated cells. Furthermore, the extracts significantly reduced TNF-α-enhanced EMPs generation in a dose-dependent manner. In conclusion, Thai perilla nutlet extracts, especially the Eth extract, may have potential to protect endothelium against vascular inflammation through the inhibition of endothelial activation and the generation of endothelial microparticles (EMPs).

Rat adipocyte apoptosis induced by TNF-α

2005 ◽  
Vol 2 (3) ◽  
pp. 149-153
Author(s):  
Lin Ya-Qiu ◽  
Li Rui-Wen ◽  
Sun Chao ◽  
Chen Guo-Zhu ◽  
Yang Yong-Qing ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Dependent Manner ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Apoptotic Effect ◽  
High Concentrations ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Dose Dependent ◽  
Necrosis Factor

AbstractThe effects of different concentrations of tumour necrosis factor-α (TNF-α) on rat adipocyte apoptosis were detected by optical microscopy, agarose gel electrophoresis and flow cytometry methods. The morphological changes of rat adipocyte apoptosis induced by TNF-α correlated linearly with the concentration of TNF-α, ranging from 5 to 20 ng/ml. High concentrations of TNF-α induced more obvious apoptosis. Significant morphological changes of rat adipocytes treated with 5 ng/ml TNF-α were noticed, but DNA ladders did not appear in the DNA electrophoresis analysis, i.e. morphological changes occurred earlier than the biochemical changes. TNF-α induced apoptosis in the rat adipocyte in a dose-dependent manner. The induced apoptotic effect of 5, 10, 15 and 20 ng/ml TNF-α was significantly different (P0.01), but the effect among 10, 15 and 20 ng/ml TNF-α treatments was not significantly different (P0.05). Thus the optimum concentration of TNF-α for inducing apoptosis was 10 ng/ml.

scholarly journals Immunological properties of human decidual macrophages – a possible role in intrauterine immunity

Reproduction ◽  
2005 ◽  
Vol 129 (5) ◽  
pp. 631-637 ◽  
Author(s):  
Uma Singh ◽  
Grant Nicholson ◽  
Britta C Urban ◽  
Ian L Sargent ◽  
Uday Kishore ◽  
...  
Keyword(s):  
Superoxide Radicals ◽  
Late Gestation ◽  
Dependent Manner ◽  
Defence Mechanisms ◽  
Tnf Α ◽  
Bacterial Lipopolysaccharides ◽  
Factor Α ◽  
Intrauterine Infections ◽  
Dose Dependent ◽  
Necrosis Factor

Our aim was to investigate the contribution of decidual macrophages, which constitute an important immune component of the decidua in late gestation, to intrauterine defence mechanisms. Using flow cytometry we examined the ability of decidual macrophages, isolated from term decidua, to bind and phagocytose fluorescence-labelled bacterial and yeast bioparticles. We also assessed their ability to generate superoxide radicals and tumour necrosis factor-α following lipopolysaccharide challenge. Decidual macrophages bound bacterial and yeast particles in a dose-dependent manner, which subsequently led to phagocytosis. These macrophages also produced superoxide radicals and the pro-inflammatory cytokine TNF-α when challenged with bacterial lipopolysaccharides. These results suggest a role for decidual macrophages in pathogen recognition and clearance during pregnancy, and, therefore, they are likely to protect the fetus against intrauterine infections which might otherwise lead to preterm labour.

Tumour necrosis factor-α gene expression and production in human umbilical arterial endothelial cells

2000 ◽  
Vol 98 (4) ◽  
pp. 461-470 ◽  
Author(s):  
Thomas NEUHAUS ◽  
Gudrun TOTZKE ◽  
Elisabeth GRUENEWALD ◽  
Hans-Peter JUESTEN ◽  
Agapios SACHINIDIS ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Dependent Manner ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Necrosis Factor

Endothelial cells act as an interface between the blood and tissues, and are known to be involved in inflammatory processes. These cells are responsive to and produce different cytokines. Tumour necrosis factor-α (TNF-α) not only is one of the most important inflammatory peptides, but also can be induced by lipopolysaccharide (LPS). The focus of the present study was on TNF-α gene expression and production in human umbilical arterial endothelial cells (HUAEC), including the kinetics of this process. Interleukin-1α (IL-1α), LPS and TNF-α, which are all known to be elevated in septic shock, were used as stimulators at concentrations commonly found in patients with sepsis. Through the use of reverse transcriptase/PCR, immunohistochemical reactions and ELISA techniques, we showed that, in HUAEC, all three stimuli were able to induce gene expression and production of TNF-α. Furthermore, this induction by IL-1α, LPS and TNF-α occurred in a time- and concentration-dependent manner in these cells. TNF-α expression and production was induced by all three agents at concentrations commonly found in patients with sepsis. TNF-α mRNA was observed within 30 min regardless of the stimulus used, but the levels peaked at different times. Since it is well established that TNF-α is able to induce the synthesis of IL-1α in endothelial cells and, as shown in the present study, TNF-α and IL-1α are themselves able to induce the synthesis of TNF-α in endothelial cells, an autocrine potentiation of cytokine release in sepsis can be proposed. This situation could lead to a locally acting ‘vicious cycle’ which, when considered in addition to the known ability of TNF-α to induce apoptosis, could mean that various organs will be damaged, a condition associated with sepsis. Thus these results provide further evidence for the important role played by the endothelium in inflammation.

Tumor necrosis factor-α decreases thyrotropin-induced 5′-deiodinase activity in FRTL-5 thyroid cells

1994 ◽  
Vol 130 (5) ◽  
pp. 502-507 ◽  
Author(s):  
Boonsong Ongphiphadhanakul ◽  
Shih Lieh Fang ◽  
Kam-Tsun Tang ◽  
Nilima A Patwardhan ◽  
Lewis E Braverman
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Dependent Manner ◽  
Thyroid Cells ◽  
Deiodinase Activity ◽  
Tnf Α ◽  
Rat Thyroid ◽  
Factor Α ◽  
Necrosis Factor

Ongphiphadhanakul B, Fang SL, Tang K-T, Patwardhan NA, Braverman LE. Tumor necrosis factor-α decreases thyrotropin-induced 5′-deiodinase activity in FRTL-5 thyroid cells. Eur J Endocrinol 1994;130:502–7. ISSN 0804–4643 Tumor necrosis factor-α (TNF-α) exerts various effects on many cell types. Acute administration of TNF-α to rats decreases hepatic 5′-deiodinase activity (5′D-I) and TNF-α has been implicated in the pathogenesis of the low triiodothyronine syndrome in non-thyroidal illness in humans. The thyroid, liver and kidney are rich in 5′D-I. Unlike hepatic and renal 5′D-I, thyroid 5′D-I is regulated by thyrotropin. We have investigated the effects of TNF-α on 5D-I in FRTL-5 cells, a cultured rat thyroid follicular cell line. Tumor necrosis factor-α did not significantly affect basal 5′D-I but thyrotropin markedly increased 5′D-I (p < 0.001). This TSH-induced increase in 5′D-I was attenuated by TNF-α in a dose-dependent manner (p < 0.001). Enzyme kinetic analysis demonstrated that thyrotropin increased 5′D-I by increasing Vmax (p < 0.01) without significantly affecting Km. Likewise, TNF-α decreased the thyrotropin-induced 5′D-I by decreasing Vmax (p < 0.05) but not Km. The effect of TNF-α on thyrotropin-induced 5′D-I in FRTL-5 cells is probably mediated through post-thyrotropin-induced generation of cyclic adenosine monophosphate (cAMP) because TNF-α inhibited both dibutyryl cAMP (p < 0.001) and forskolin (p < 0.001)-induced increases in 5′D-I without affecting cAMP generation stimulated by thyrotropin. In conclusion, we have demonstrated that TNF-α inhibits thyrotropininduced 5′D-I activity in FRTL-5 cells by pathways distal to the generation of cAMP and that TNF-α may play a role in the modulation of the production of triiodothyronine by the thyroid gland. Furthermore, the increase in TNF-α observed in patients with the euthyroid sick syndrome may contribute to the low serum triiodothyronine observed in these patients, not only by inhibiting peripheral generation of triiodothyronine from thyroxine but also by decreasing thyroidal generation and subsequent secretion of triiodothyronine. Lewis E Braverman, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA

scholarly journals Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats

2021 ◽  
Vol 16 (1) ◽  
pp. 128-141
Author(s):  
Gang Xiao ◽  
Mei Zhang ◽  
Xing Peng ◽  
Guangyuan Jiang
Keyword(s):  
Signaling Pathways ◽  
Cerebral Aneurysm ◽  
Protocatechuic Acid ◽  
Inflammatory Responses ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Protective Effects ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract Our current research aims to examine whether protocatechuic acid (PCA) can be used as a therapeutic agent for the development of cerebral aneurysm (CA) and to elucidate the mechanisms behind this. We assessed the effects of PCA at 50 and 100 mg/kg on the activation of signaling pathways for tissue necrosis factor (TNF)-α/nuclear factor (NF)-κB/nuclear factor erythroid 2 (Nrf-2) on progression and development in an elastase-induced CA model, accompanied by a high-salt diet to induce hypertension. The expression of inflammatory cytokines, chemokines, tumor necrosis factor-α, interleukins (IL)-8, IL-17, IL-6, IL-1β, and matrix metalloproteinase (MMP)-2 and MMP-9 was analyzed by ELISA, western blot, and reverse transcriptase quantative polymerase chain reaction. The expression levels of antioxidant enzymes and translocation of Nrf-2 were also determined. The group treated with PCA demonstrated a significant (P < 0.05) decrease in the aneurysmal size in rats compared to the CA-induced group. We found that PCA treatment suppressed the invasion of macrophage and activation of TNF-α/NF-κB/Nrf-2 signaling pathways. There was a significant decrease (P < 0.05) in pro-inflammatory cytokine and chemokine levels in a dose-dependent manner. We found that PCA treatment exerts protective effects by suppressing the development and progression of CA through the inhibition of inflammatory responses in macrophages via TNF-α/NF-κB/Nrf-2 signaling pathways, thus demonstrating that PCA can act as a treatment for CA.

scholarly journals The Wnt/β-Catenin Pathway Regulated Cytokines for Pathological Neuropathic Pain in Chronic Compression of Dorsal Root Ganglion Model

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Ye Zhang ◽  
Dan Zhao ◽  
Xutong Li ◽  
Beiyao Gao ◽  
Chengcheng Sun ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Critical Role ◽  
Spinal Cord Dorsal Horn ◽  
Rat Serum ◽  
Tnf Α ◽  
Spinal Cord Dorsal ◽  
Factor Α ◽  
Necrosis Factor

Neuropathic pain is one of the important challenges in the clinic. Although a lot of research has been done on neuropathic pain (NP), the molecular mechanism is still elusive. We aimed to investigate whether the Wnt/β-catenin pathway was involved in NP caused by sustaining dorsal root ganglion (DRG) compression with the chronic compression of dorsal root ganglion model (CCD). Our RNA sequencing results showed that several genes related to the Wnt pathway have changed in DRG and spinal cord dorsal horn (SCDH) after CCD surgery. Therefore, we detected the activation of the Wnt/β-catenin pathway in DRG and SCDH and found active β-catenin significantly upregulated in DRG and SCDH 1 day after CCD surgery and peaked on days 7-14. Immunofluorescence results also confirmed nuclear translocalization of active β-catenin in DRG and SCDH. Additionally, rats had obvious mechanical induced pain after CCD surgery and the pain was significantly alleviated after the application of the Wnt/β-catenin pathway inhibitor XAV939. Furthermore, we found that the levels of proinflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were significantly elevated in CCD rat serum, while the levels of them were correspondingly decreased after the Wnt/β-catenin pathway being inhibited. The results of Spearman correlation coefficient analysis showed that the levels of TNF-α and IL-18 were negatively correlated with the mechanical withdrawal thresholds (MWT) after CCD surgery. Collectively, our findings suggest that the Wnt/β-catenin pathway plays a critical role in the pathogenesis of NP and may be an effective target for the treatment of NP.

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