A role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling in the human neutrophil

2002 ◽  
Vol 283 (1) ◽  
pp. C48-C57 ◽  
Author(s):  
Laurie E. Kilpatrick ◽  
Julia Y. Lee ◽  
Kathleen M. Haines ◽  
Donald E. Campbell ◽  
Kathleen E. Sullivan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Proinflammatory Cytokine ◽  
Tumor Necrosis ◽  
Spontaneous Apoptosis ◽  
Kinase C ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Transcription Factor Nfκb ◽  
Necrosis Factor

The proinflammatory cytokine tumor necrosis factor (TNF)-α has been implicated in the attenuation of neutrophil spontaneous apoptosis during sepsis. Antiapoptotic signaling is principally mediated through the p60TNF receptor (p60TNFR). In neutrophils, TNF-α is an incomplete secretagogue and requires input from a ligated integrin(s) for neutrophil activation. In adherent neutrophils, TNF-α triggers association of both protein kinase C (PKC)-δ and phosphatidylinositol (PI) 3-kinase with the p60TNFR. In this study, a role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling was examined. TNF-α inhibited spontaneous apoptosis in fibronectin-adherent neutrophils, and this antiapoptotic signaling was blocked by the PKC-δ inhibitor rottlerin, but not by an inhibitor of Ca2+-dependent PKC isotypes, Go-6976. Inhibition of PI 3-kinase by LY-294002 also inhibited TNF-α-mediated antiapoptotic signaling. Cycloheximide blocked TNF-α-mediated antiapoptotic signaling, suggesting protein synthesis is required. Inhibition of either PKC-δ or PI 3-kinase attenuated TNF-α-mediated activation of the antiapoptotic transcription factor NFκB. Thus both PKC-δ and PI 3-kinase have essential roles in TNF-α-mediated antiapoptotic signaling in adherent neutrophils.

scholarly journals Surface engineering of porous silicon to optimise therapeutic antibody loading and release

2015 ◽  
Vol 3 (20) ◽  
pp. 4123-4133 ◽  
Author(s):  
Steven J. P. McInnes ◽  
Chris T. Turner ◽  
Sameer A. Al-Bataineh ◽  
Marta J. I. Airaghi Leccardi ◽  
Yazad Irani ◽  
...  
Keyword(s):  
Porous Silicon ◽  
Proinflammatory Cytokine ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Surface Engineering ◽  
Chronic Wounds ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Necrosis Factor

Infliximab antibodies released from porous silicon microparticles can sequester the proinflammatory cytokine, tumor necrosis factor-α (TNF-α), which is elevated in uveitis and non-healing chronic wounds.

scholarly journals iRhom2 and TNF: Partners or enemies?

2019 ◽  
Vol 12 (605) ◽  
pp. eaaz0444 ◽  
Author(s):  
Marina Badenes ◽  
Colin Adrain
Keyword(s):  
Hepatic Stellate Cells ◽  
Proinflammatory Cytokine ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Stellate Cells ◽  
Protective Role ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Necrosis Factor

iRhom2 is an essential cofactor for ADAM17, the metalloprotease that sheds both the proinflammatory cytokine tumor necrosis factor–α (TNF-α) and TNF receptors (TNFRs) from the cell surface. In this issue of Science Signaling, Sundaram et al. demonstrate a protective role for iRhom2 in promoting ADAM17-mediated shedding of TNFRs in hepatic stellate cells, which reduces TNFR signaling and liver fibrosis in response to injury.

Epinephrine inhibits endotoxin-induced IL-1β production: roles of tumor necrosis factor-α and IL-10

1997 ◽  
Vol 273 (6) ◽  
pp. R1885-R1890 ◽  
Author(s):  
Tom Van Der Poll ◽  
Stephen F. Lowry
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Systemic Infection ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Dose Dependent Decrease ◽  
Factor Α ◽  
Necrosis Factor

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-α and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1β production, the following experiments were performed: 1) blood obtained from subjects at 4–21 h after the start of a continuous infusion of epinephrine (30 ng ⋅ kg−1⋅ min−1) produced less IL-1β after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1β production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1β production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.

scholarly journals Yersinia enterocolitica Impairs Activation of Transcription Factor NF-κB: Involvement in the Induction of Programmed Cell Death and in the Suppression of the Macrophage Tumor Necrosis Factor α Production

1998 ◽  
Vol 187 (7) ◽  
pp. 1069-1079 ◽  
Author(s):  
Klaus Ruckdeschel ◽  
Suzanne Harb ◽  
Andreas Roggenkamp ◽  
Mathias Hornef ◽  
Robert Zumbihl ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Tumor Necrosis Factor ◽  
Programmed Cell Death ◽  
Proteasome Inhibitor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

In this study, we investigated the activity of transcription factor NF-κB in macrophages infected with Yersinia enterocolitica. Although triggering initially a weak NF-κB signal, Y. enterocolitica inhibited NF-κB activation in murine J774A.1 and peritoneal macrophages within 60 to 90 min. Simultaneously, Y. enterocolitica prevented prolonged degradation of the inhibitory proteins IκB-α and IκB-β observed by treatment with lipopolysaccharide (LPS) or nonvirulent, plasmid-cured yersiniae. Analysis of different Y. enterocolitica mutants revealed a striking correlation between the abilities of these strains to inhibit NF-κB and to suppress the tumor necrosis factor α (TNF-α) production as well as to trigger macrophage apoptosis. When NF-κB activation was prevented by the proteasome inhibitor MG-132, nonvirulent yersiniae as well as LPS became able to trigger J774A.1 cell apoptosis and inhibition of the TNF-α secretion. Y. enterocolitica also impaired the activity of NF-κB in epithelial HeLa cells. Although neither Y. enterocolitica nor TNF-α could induce HeLa cell apoptosis alone, TNF-α provoked apoptosis when activation of NF-κB was inhibited by Yersinia infection or by the proteasome inhibitor MG-132. Together, these data demonstrate that Y. enterocolitica suppresses cellular activation of NF-κB, which inhibits TNF-α release and triggers apoptosis in macrophages. Our results also suggest that Yersinia infection confers susceptibility to programmed cell death to other cell types, provided that the appropriate death signal is delivered.

Stimulation of protein kinase C activity by tumor necrosis factor-α in bovine bronchial epithelial cells

1997 ◽  
Vol 273 (5) ◽  
pp. L1007-L1012 ◽  
Author(s):  
Todd A. Wyatt ◽  
Harumasa Ito ◽  
Thomas J. Veys ◽  
John R. Spurzem
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Epithelial Cells ◽  
Tumor Necrosis ◽  
Bronchial Epithelial ◽  
Calphostin C ◽  
Kinase C ◽  
Tnf Α ◽  
Necrosis Factor

Bronchial epithelial cell migration, attachment, and proliferation are important processes in response to airway injury. We have shown that tumor necrosis factor (TNF)-α stimulates the migration of bovine bronchial epithelial cells (BBEC) in vitro. We hypothesized that protein kinase C (PKC) may be one of the intracellular signaling mediators of TNF-α in BBEC. In this study, we have identified multiple PKC isoforms in BBEC and measured total cellular PKC activity. Polyclonal antibodies to the PKC-α, -β2, -δ, and -ε isoforms recognized protein bands around 80–90 kDa. BBEC primary cultures treated with either 500 U/ml TNF-α for 2–4 h or 100 ng/ml 12- O-tetradecanoylphorbol 13-acetate for 15 min resulted in three- to fivefold increases in PKC activity in the particulate fractions of crude cell lysates. This activity was inhibited by 1 μM calphostin C or 10 μM H-7. Similarly, TNF-α-stimulated BBEC migration was reduced at least twofold in the presence of H-7 or calphostin C. These studies suggest that the activation of PKC is necessary for TNF-α-stimulated BBEC migration.

Increase of Mucous Glycoprotein Secretion by Tumor Necrosis Factor Alpha via a Protein Kinase C-Dependent Mechanism in Cultured Chinchilla Middle Ear Epithelial Cells

1998 ◽  
Vol 107 (3) ◽  
pp. 213-219 ◽  
Author(s):  
Jizhen Lin ◽  
Youngki Kim ◽  
Steven K. Juhn
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Epithelial Cells ◽  
Middle Ear ◽  
Tumor Necrosis ◽  
Kinase C ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Dependent Mechanism

Tumor necrosis factor α (TNF-α), originally defined by its antitumoral activity, is now recognized as a polypeptide mediator of inflammatory and cellular immune response. Recent studies have demonstrated that TNF-α exists in the fluid of otitis media with effusion and, therefore, suggested its possible role in the pathogenesis of mucus hypersecretion. In this study, the effects of TNF-α on mucous glycoprotein (MGP) secretion from cultured chinchilla middle ear epithelial cells were examined, and TNF-α was found to stimulate MGP secretion in a time- and concentration-dependent manner. The action of TNF-α on MGP secretion was significantly and dose-dependently inhibited by TNF-α monoclonal antibody; this finding is suggestive of its specificity on MGP secretion. The addition of the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperidine (H-7) to the culture significantly blocked TNF-α-induced MGP secretion, while the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) did not. This suggests that TNF-α stimulates MGP secretion via a protein kinase C—dependent mechanism.

Inhibition of TNF-α Promoter Activity and Synthesis by A11-99-1, a New Cyclopentenone from the Ascomycete Mollisia melaleuca

2005 ◽  
Vol 60 (5-6) ◽  
pp. 478-484 ◽  
Author(s):  
Jan Rether ◽  
Gerhard Erkel ◽  
Olov Sterner ◽  
Timm Anke
Keyword(s):  
Transcription Factor ◽  
Tumor Necrosis ◽  
Promoter Activity ◽  
Tumor Necrosis Factor Α ◽  
Spectroscopic Techniques ◽  
Antibacterial And Antifungal Activities ◽  
Tnf Α ◽  
Factor Α ◽  
Antibacterial And Antifungal ◽  
Necrosis Factor

In a search for inhibitors of the inducible tumor necrosis factor-α (TNF-α) promoter activity and synthesis, a new chlorinated cyclopentenone was isolated from fermentations of the ascomycete Mollisia melaleuca. The structure was determined by a combination of spectroscopic techniques. The compound blocked the inducible human TNF-α promoter activity and synthesis with IC50-values of 2.5-5 μg/ml (8.1-16.1 μм). Studies on the mode of action of the compound revealed that the inhibition of TNF-α promoter activity is caused by an inhibition of the phosphorylation of the IϰB protein which prevents the activation of the transcription factor NF-ϰB. No cytotoxic, antibacterial and antifungal activities could be observed up to 100 μg/ml (323 μм) of the compound.

scholarly journals The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-κβ System

2006 ◽  
Vol 13 (3) ◽  
pp. 319-328 ◽  
Author(s):  
Madhavan P. Nair ◽  
Supriya Mahajan ◽  
Jessica L. Reynolds ◽  
Ravikumar Aalinkeel ◽  
Harikrishnan Nair ◽  
...  
Keyword(s):  
Gene Expression ◽  
Proinflammatory Cytokine ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

ABSTRACT The flavonoids comprise a large class of low-molecular-weight plant metabolites ubiquitously distributed in food plants. These dietary antioxidants exert significant antitumor, antiallergic, and anti-inflammatory effects. The molecular mechanisms of their biological effects remain to be clearly understood. We investigated the anti-inflammatory potentials of a safe, common dietary flavonoid component, quercetin, for its ability to modulate the production and gene expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) by human peripheral blood mononuclear cells (PBMC). Our results showed that quercetin significantly inhibited TNF-α production and gene expression in a dose-dependent manner. Our results provide direct evidence of the anti-inflammatory effects of quercetin by PBMC, which are mediated by the inhibition of the proinflammatory cytokine TNF-α via modulation of NF-κβ1 and Iκβ.

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