Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production.

ABSTRACT: Tumor necrosis factor (TNF)-α is a major pro-inflammatory cytokine produced in response to toll-like receptor stimulation. TNF-α release is controlled by the activity of TNF-α converting enzyme (TACE) that cut membrane-bound TNF-α to shed its ectodomain as a soluble cytokine. The purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is activated in response to elevated concentrations of extracellular ATP and induces different pro-inflammatory pathways in macrophages to establish an inflammatory response. P2X7 receptor promotes the activation of the inflammasome and the release of interleukin-1β, the production of inflammatory lipids, and the generation of reactive oxygen species. In this study, we analyzed the mechanism of P2X7 receptor responsible of TNF-α release after priming macrophages with LPS doses ≤100 ng/ml. We found that P2X7 receptor increases the extracellular activity of TACE through the release of the mature form of TACE in exosomes. This effect was blocked using P2X7 receptor inhibitors or in macrophages obtained from P2X7 receptor-deficient mice. Elevation of intracellular Ca2+ and p38 mitogen-activated protein kinase after P2X7 receptor activation were involved in the release of TACE, which was able to process TNF-α on nearby expressing cells. Finally, we observed an increase of TNF-α in the peritoneal lavage of mice treated with LPS and ATP. In conclusion, P2X7 receptor induces the release of TACE in exosomes to the extracellular compartment that could amplify the pro-inflammatory signal associated to this receptor. These results are important for the development of therapeutics targeting P2X7 receptor.

SUBMITTER: Barbera-Cremades M

PROVIDER: S-EPMC5523084 | biostudies-other | 2017

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.

Project description:G protein-coupled receptors induce EGF receptor (EGFR) signaling, leading to the proliferation and invasion of cancer cells. Elucidation of the mechanism of EGFR activation by G protein-coupled receptors may identify new signaling paradigms. A gastrin-releasing peptide (GRP)/GRP receptor-mediated autocrine pathway was previously described in squamous cell carcinoma of head and neck. In the present study, we demonstrate that TNF-alpha converting enzyme (TACE), a disintegrin and metalloproteinse-17, undergoes a Src-dependent phosphorylation that regulates release of the EGFR ligand amphiregulin upon GRP treatment. Further investigation reveals the phosphatidylinositol 3-kinase (PI3-K) as the intermediate of c-Src and TACE, contributing to their association and TACE phosphorylation. Phosphoinositide-dependent kinase 1 (PDK1), a downstream target of PI3-K, has been identified as the previously undescribed kinase to directly phosphorylate TACE upon GRP treatment. These findings suggest a signaling cascade of GRP-Src-PI3-K-PDK1-TACE-amphiregulin-EGFR with multiple points of interaction, translocation, and phosphorylation. Furthermore, knockdown of PDK1 augmented the antitumor effects of the EGFR inhibitor erlotinib, indicating PDK1 as a therapeutic target to improve the clinical response to EGFR inhibitors.

| S-EPMC1458991 | biostudies-literature

Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry.

Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV) is a high-risk infectious pathogen. In the proposed model of respiratory failure, SARS-CoV down-regulates its receptor, angiotensin-converting enzyme 2 (ACE2), but the mechanism involved is unknown. We found that the spike protein of SARS-CoV (SARS-S) induced TNF-alpha-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain. The modulation of TACE activity by SARS-S depended on the cytoplasmic domain of ACE2, because deletion mutants of ACE2 lacking the carboxyl-terminal region did not induce ACE2 shedding or TNF-alpha production. In contrast, the spike protein of HNL63-CoV (NL63-S), a CoV that uses ACE2 as a receptor and mainly induces the common cold, caused neither of these cellular responses. Intriguingly, viral infection, judged by real-time RT-PCR analysis of SARS-CoV mRNA expression, was significantly attenuated by deletion of the cytoplasmic tail of ACE2 or knock-down of TACE expression by siRNA. These data suggest that cellular signals triggered by the interaction of SARS-CoV with ACE2 are positively involved in viral entry but lead to tissue damage. These findings may lead to the development of anti-SARS-CoV agents.

| S-EPMC2409424 | biostudies-literature

Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17).

Project description:Peripheral serotonin (5-hydroxytryptamine, 5-HT) is transported by platelets and released upon stimulation. In the platelet cytoplasm, 5-HT is transamidated to small GTPases, promoting alpha-granule release and primary hemostasis.We hypothesized that 5-HT could also stimulate platelet receptor shedding after binding to the membrane 5-HT receptor (5-HT2AR).Western blot and flow cytometry were used to determine levels of the adhesion receptor glycoprotein (GP)Ibalpha on platelets or its shed fragment glycocalicin in plasma and serum from wild-type mice, Tph1(-/-) mice lacking peripheral 5-HT, and mice lacking functional tumor necrosis factor-alpha-converting enzyme (TACE, ADAM17). Flow chamber experiments and intravital microscopy were used to examine the adhesive properties of platelets after stimulation of 5-HT2AR.Glycocalicin was significantly reduced in Tph1(-/-) plasma and serum. In isolated platelets, 5-HT induced shedding of GPIbalpha, which was increased to 60% when 5-HT uptake was inhibited by the selective serotonin reuptake inhibitor fluoxetine. Specific 5-HT2AR agonism and antagonism suggested activation of this receptor. The shedding could not be induced in TACE(DeltaZn/DeltaZn) platelets, suggesting that activated TACE mediated the shedding of GPIbalpha. Intracellular signaling involved phosphorylation of p38 mitogen-activated protein kinase rather than G-protein signaling. 5-HT2AR stimulation decreased platelet adhesion to collagen-bound von Willebrand factor under arterial shear (1500 s(-1)) and incorporation into FeCl3-induced thrombi in mesenteric arterioles.Stimulation of 5-HT2AR on platelets induces TACE-mediated shedding of GPIbalpha, the key adhesion molecule under high shear conditions. Our observations demonstrate a new pathway through which 5-HT could modulate cardiovascular disease.

| S-EPMC3244876 | biostudies-literature

Sequential proteolytic processing of an interferon-alpha receptor subunit by TNF-alpha converting enzyme and presenilins.

Project description:It is well established that interferons trigger tyrosine-kinase-dependent signaling via JAK kinases and STAT transcription factors. However, we have observed both IFNaR2 receptor cleavage and functional activity of the liberated intracellular domain (ICD), suggesting that interferon-alpha (IFN-alpha) can also signal via regulated intramembrane proteolysis (RIP), an evolutionarily conserved mechanism of receptor-mediated signaling. Sequential cleavage of the receptor ectodomain and transmembrane domain is a hallmark of the most common class of RIP. To investigate the mechanisms of IFNaR2 RIP signaling, we examined IFNaR2 cleavage by TNF-alpha converting enzyme (TACE) and presenilin proteases. We tracked the fate of epitope-tagged and fusion variants of IFNaR2 in cells expressing wild-type, mutant, or null versions of TACE and presenilins 1 and 2. Cleavage and subcellular location were determined by immunoblot, fluoresence microscopy, and reporter assays. We found that both TACE and presenilin 1/2 cleave IFNaR2, in a sequential manner that allows the ICD to move to the nucleus. TACE cleavage was induced by IFN-alpha but was not consistently required for the anti-proliferative effects of IFN-alpha. In conclusion, IFNaR2 is cleaved by TACE and Presenilin 1/2, suggesting that interferons signal by both kinase and RIP-mediated pathways.

| S-EPMC3390988 | biostudies-literature

Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release.

Project description:Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca(2+) influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.

| S-EPMC4423803 | biostudies-literature

Sitafloxacin reduces tumor necrosis factor alpha (TNFα) converting enzyme (TACE) phosphorylation and activity to inhibit TNFα release from lipopolysaccharide-stimulated THP-1 cells.

Project description:Sepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.

| S-EPMC8683466 | biostudies-literature

Brain TACE (Tumor Necrosis Factor-α-Converting Enzyme) Contributes to Sympathetic Excitation in Heart Failure Rats.

Project description:TNF-α (tumor necrosis factor-α) is initially synthesized as a transmembrane protein that is cleaved by TACE (TNF-α-converting enzyme) to release soluble TNF-α. The elevated level of TNF-α in the brain and circulation in heart failure (HF) suggests an increase in the TACE-mediated ectodomain shedding process. The present study sought to determine whether TACE is upregulated in cardiovascular/autonomic brain regions like subfornical organ and hypothalamic paraventricular nucleus in rats with ischemia-induced HF and whether TACE plays a role in TNF-α-driven sympathetic excitation. We found that TACE was expressed throughout the subfornical organ and paraventricular nucleus, with significantly higher levels in HF than in sham-operated (Sham) rats. Intracerebroventricular injection of recombinant TACE induced a mild increase in blood pressure, heart rate, and renal sympathetic nerve activity that peaked at 15 to 20 minutes in both Sham and HF rats. HF rats had a secondary prolonged increase in these variables that was prevented by the TNF-α inhibitor SPD304. Intracerebroventricular administration of the TACE inhibitor TNF-alpha protease inhibitor 1 decreased blood pressure, heart rate, and renal sympathetic nerve activity in Sham and HF rats, with an exaggerated reduction in heart rate and renal sympathetic nerve activity in the HF rats. Direct microinjection of TACE or TNF-alpha protease inhibitor 1 into paraventricular nucleus or subfornical organ of Sham and HF rats elicited blood pressure, heart rate, and renal sympathetic nerve activity responses similar to intracerebroventricular TACE or TNF-alpha protease inhibitor 1. Intracerebroventricular infusion of Ang II (angiotensin II) and IL (interleukin)-1β increased TACE expression in subfornical organ and paraventricular nucleus of normal rats. These data suggest that a TACE-mediated increase in soluble TNF-α in the brain contributes to sympathetic excitation in HF.

| S-EPMC6639045 | biostudies-literature

Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells.

Project description:Ectodomain shedding of epidermal growth factor receptor (EGFR) ligands [e.g., transforming growth factor type alpha (TGF-alpha)] and EGFR phosphorylation are implicated in mucin production in airway epithelial cells. Tumor necrosis factor alpha-converting enzyme (TACE) is reported to cleave precursor of TGF-alpha, with release of soluble mature TGF-alpha in various epithelial tissues. We hypothesized that TACE increases the shedding of TGF-alpha, resulting in EGFR phosphorylation and inducing mucin production in human airway epithelial (NCI-H292) cells. To examine this hypothesis, we stimulated NCI-H292 cells with phorbol 12-myristate 13-acetate (PMA, an activator of TACE) and pathophysiologic stimuli [lipopolysaccharide (LPS) and supernatant from the Gram-negative bacterium Pseudomonas aeruginosa (PA sup)]. PMA, PA sup, and LPS increased MUC5AC gene expression and mucin protein production, effects that were prevented by pretreatment with AG1478, a selective inhibitor of EGFR phosphorylation and by preincubation with an EGFR-neutralizing Ab or with a TGF-alpha-neutralizing Ab, implicating ligand (TGF-alpha)-dependent EGFR phosphorylation in mucin production. These stimuli induced release of soluble TGF-alpha, EGFR phosphorylation, and MUC5AC expression, which were blocked by the metalloprotease inhibitors tumor necrosis factor-alpha protease inhibitor-1 and tissue inhibitor of metalloprotease-3. We specifically knocked down the expression of metalloprotease TACE by using small interfering RNA for TACE. Knockdown of TACE inhibited PMA-, PA sup-, and LPS-induced TGF-alpha shedding, EGFR phosphorylation, and mucin production. From these results, we conclude that TACE plays a critical role in mucin production by airway epithelial cells by means of a TACE ligand-EGFR cascade in response to various stimuli.

| S-EPMC208807 | biostudies-literature

Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease.

Project description:Transforming growth factor-alpha (TGF-alpha) is abnormally expressed in autosomal recessive polycystic kidney disease (ARPKD). Tumor necrosis factor-alpha converting enzyme (TACE), a metalloproteinase, mediates TGF-alpha processing. In this study, we sought to determine whether TGF-alpha was an absolute requirement for renal cystogenesis and whether its absence would modulate disease severity or related growth factors/receptors expression. Bpk heterozygotes were bred with TGF-alpha null mice to produce cystic and noncystic offspring with or without TGF-alpha. Assessments included kidney weight (KW), body weight (BW), blood urea nitrogen (BUN), and kidney and liver immunohistology. Western analysis assessed kidney expression of amphiregulin (AR), epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), and their receptors, EGFR and ErbB4. A PCR-based methodology for genotyping bpk mice was also developed. No significant differences in KW, BW, KW/BW%, or BUN were seen in cystic mice with versus without TGF-alpha. Cystic kidney disease and liver disease histology were similar. AR, EGF, HB-EGF, EGFR, and ErbB4 were abnormally expressed to an equal degree in kidneys of mice with versus without TGF-alpha. Although previous data suggest a critical role of TGF-alpha in murine PKD, these data show that TGF-alpha is not required for renal cyst formation or kidney or liver disease progression. We speculate that the therapeutic effect of WTACE2 could have been due to effects on several TACE targets, including TGF-alpha, AR, and ErbB4, as well as metalloproteinases other than TACE.

| S-EPMC1570100 | biostudies-literature

The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release.

Project description:Background and purposeUsing an in-house bioinformatics programme, we identified and synthesized a novel nonapeptide, H-Pro-Pro-Thr-Thr-Thr-Lys-Phe-Ala-Ala-OH. Here, we have studied its biological activity, in vitro and in vivo, and have identified its target in the brain.Experimental approachThe affinity of the peptide was characterized using purified whole brain and striatal membranes from guinea pigs and rats . Its effect on behaviour in rats following intra-striatal injection of the peptide was investigated. A photoaffinity UV cross-linking approach combined with subsequent affinity purification of the ligand covalently bound to its receptor allowed identification of its target.Key resultsThe peptide bound with high affinity to a single class of binding sites, specifically localized in the striatum and substantia nigra of brains from guinea pigs and rats. When injected within the striatum of rats, the peptide stimulated in vitro and in vivo dopamine release and induced dopamine-like motor effects. We purified the target of the peptide, a ~151 kDa protein that was identified by MS/MS as angiotensin converting enzyme (ACE I). Therefore, we decided to name the peptide acein.Conclusion and implicationsThe synthetic nonapeptide acein interacted with high affinity with brain membrane-bound ACE. This interaction occurs at a different site from the active site involved in the well-known peptidase activity, without modifying the peptidase activity. Acein, in vitro and in vivo, significantly increased stimulated release of dopamine from the brain. These results suggest a more important role for brain ACE than initially suspected.

| S-EPMC4940823 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data