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 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.

Characterization of rabbit SP-B promoter region responsive to downregulation by tumor necrosis factor-α

2000 ◽  
Vol 279 (5) ◽  
pp. L806-L814 ◽  
Author(s):  
Kiflu Berhane ◽  
Ramgopal K. Margana ◽  
Vijayakumar Boggaram
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Promoter Activity ◽  
Tumor Necrosis Factor Α ◽  
Surfactant Protein ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Nuclear Levels ◽  
Factor Α ◽  
Necrosis Factor

Surfactant protein B (SP-B) is essential for the maintenance of biophysical properties and physiological function of pulmonary surfactant. Tumor necrosis factor-α (TNF-α), an important mediator of lung inflammation, inhibits surfactant phospholipid and surfactant protein synthesis in the lung. In the present study, we investigated the TNF-α inhibition of rabbit SP-B promoter activity in a human lung adenocarcinoma cell line (NCI-H441). Deletion experiments indicated that the TNF-α response elements are located within −236 bp of SP-B 5′-flanking DNA. The TNF-α response region contained binding sites for nuclear factor-κB (NF-κB), Sp1/Sp3, thyroid transcription factor (TTF)-1, and hepatocyte nuclear factor (HNF)-3 transcription factors. Inhibitors of NF-κB activation such as dexamethasone and N-tosyl-l-phenylalanine chloromethyl ketone and mutation of the NF-κB element did not reverse TNF-α inhibition of SP-B promoter, indicating that TNF-α inhibition of SP-B promoter activity occurs independently of NF-κB activation. TNF-α treatment decreased the binding activities of TTF-1 and HNF-3 elements without altering the nuclear levels of TTF-1 and HNF-3α proteins. Pretreatment of cells with okadaic acid reversed TNF-α inhibition of SP-B promoter activity. Taken together these data indicated that in NCI-H441 cells 1) TNF-α inhibition of SP-B promoter activity may be caused by decreased binding activities of TTF-1 and HNF-3 elements, 2) the decreased binding activities of TTF-1 and HNF-3α are not due to decreased nuclear levels of the proteins, and 3) okadaic acid-sensitive phosphatases may be involved in mediating TNF-α inhibition of SP-B promoter activity.

Effect of tumor necrosis factor-α and interleukin-1α on heme oxygenase-1 expression in human endothelial cells

1998 ◽  
Vol 274 (3) ◽  
pp. H883-H891 ◽  
Author(s):  
Christi M. Terry ◽  
Jennifer A. Clikeman ◽  
John R. Hoidal ◽  
Karleen S. Callahan
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Heme Oxygenase ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Heme Oxygenase 1 ◽  
Human Endothelial Cells ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Heme iron exacerbates oxidant damage by catalyzing the production of free radicals. Heme oxygenase is the rate-limiting enzyme involved in heme catabolism. An inducible form of heme oxygenase, heme oxygenase-1 (HO-1), is upregulated in oxidant and inflammatory settings, and recent work suggests that HO-1 induction may serve a protective function against oxidant injury. The ability of the endogenous inflammatory mediators, interleukin (IL)-1α, tumor necrosis factor-α (TNF-α), and IL-6, to enhance HO-1 expression in cultured human endothelial cells was examined in this study. HO-1 mRNA and protein expression were upregulated by IL-1α and TNF-α exposure but not by IL-6. Induction of HO-1 mRNA by IL-1α and TNF-α occurred in a concentration- and time-dependent fashion, with maximal expression occurring by 4 h for both cytokines. Induction depended on protein synthesis and occurred at the transcriptional level. Inhibition of the AP-1 transcription factor with curcumin decreased the cytokine induction of HO-1 mRNA, suggesting the involvement of this transcription factor in cytokine signaling of HO-1. The results of this study indicate that the endogenous inflammatory cytokines IL-1α and TNF-α induce HO-1 in endothelial cells, providing further evidence that HO-1 may be an important cellular response to inflammatory stress.

#50 Gestational exposure of tumor necrosis factor-α (TNF-α) inhibitor drugs

2019 ◽  
Vol 88 ◽  
pp. 149-150 ◽  
Author(s):  
Erkoseoglu Ilknur ◽  
Kadioglu Mine ◽  
Cavusoglu Irem ◽  
Sisman Mulkiye ◽  
Aran Turhan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Gestational Exposure ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Tumor necrosis factor α Inhibition for Alzheimer’s Disease

2017 ◽  
Vol 9 ◽  
pp. 117957351770927 ◽  
Author(s):  
Rudy Chang ◽  
Kei-Lwun Yee ◽  
Rachita K Sumbria
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Short Review ◽  
Tnf Α ◽  
Factor Α ◽  
Ad Therapy ◽  
Necrosis Factor

Tumor necrosis factor α (TNF-α) plays a central role in the pathophysiology of Alzheimer’s disease (AD). Food and Drug Administration–approved biologic TNF-α inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-α in AD, challenges associated with the development of existing biologic TNF-α inhibitors for AD, and potential therapeutic strategies for targeting TNF-α for AD therapy.

Tumor necrosis factor-α-associated lysosomal permeabilization is cathepsin B dependent

2002 ◽  
Vol 283 (4) ◽  
pp. G947-G956 ◽  
Author(s):  
Nathan W. Werneburg ◽  
M. Eugenia Guicciardi ◽  
Steven F. Bronk ◽  
Gregory J. Gores
Keyword(s):  
Tumor Necrosis Factor ◽  
Cathepsin B ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Fluorescent Protein ◽  
Tnf Α ◽  
Calcein Release ◽  
Green Fluorescent ◽  
Factor Α ◽  
Necrosis Factor

Cathepsin B (Cat B) is released from lysososomes during tumor necrosis factor-α (TNF-α) cytotoxic signaling in hepatocytes and contributes to cell death. Sphingosine has recently been implicated in lysosomal permeabilization and is increased in the liver by TNF-α. Thus the aims of this study were to examine the mechanisms involved in TNF-α-associated lysosomal permeabilization, especially the role of sphingosine. Confocal microscopy demonstrated Cat B-green fluorescent protein and LysoTracker Red were both released from lysosomes after treatment of McNtcp.24 cells with TNF-α/actinomycin D, a finding compatible with lysosomal destabilization. In contrast, endosomes labeled with Texas Red dextran remained intact, suggesting lysosomes were specifically targeted for permeabilization. LysoTracker Red was released from lysosomes in hepatocytes treated with TNF-α or sphingosine in Cat B(+/+) but not Cat B(−/−) hepatocytes, as assessed by a fluorescence-based assay. With the use of a calcein release assay in isolated lysosomes, sphingosine permeabilized liver lysosomes isolated from Cat B(+/+) but not Cat B(−/−) liver. C6ceramide did not permeabilize lysosomes. In conclusion, these data implicate a sphingosine-Cat B interaction inducing lysosomal destabilization during TNF-α cytotoxic signaling.

Tumor Necrosis Factor-α −308 Genotypes Influence Inflammatory Activity and TNF-α Serum Concentrations in Children with Juvenile Idiopathic Arthritis

2009 ◽  
Vol 36 (4) ◽  
pp. 837-842 ◽  
Author(s):  
ANA FILIPA MOURÃO ◽  
JOANA CAETANO-LOPES ◽  
PAULA COSTA ◽  
HELENA CANHÃO ◽  
MARIA JOSÉ SANTOS ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Tumor Necrosis Factor ◽  
Disease Activity ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Inflammatory Activity ◽  
Serum Concentrations ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Objective.Considering the relevance of tumor necrosis factor-α (TNF-α) in the pathophysiology of juvenile idiopathic arthritis (JIA), it is likely that polymorphisms in its promoter area may be relevant in disease susceptibility and activity. We investigated if clinical measures of JIA activity and TNF-α serum concentrations were associated with TNF-α −308 genotypes.Methods.Portuguese patients with JIA in 5 pediatric rheumatology centers were recruited consecutively, along with a control group of healthy subjects. Demographic and clinical data and blood samples were collected from each patient. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at position −308 by restriction fragment-length polymorphism.Results.One hundred fourteen patients and 117 controls were evaluated; 57% of patients presented the oligoarticular subtype, 25% the polyarticular subtype, 8% the systemic subtype, and 9% had enthesitis-related arthritis and 5% psoriatic arthritis. Twenty-four percent of the patients presented the −308 GA/AA genotypes and 76% the −308 GG genotype, similar to findings in controls. Patients with the −308 GA/AA genotype had higher degree of functional impairment, erythrocyte sedimentation rate, 100-mm visual analog scale score for disease activity, and TNF-α levels compared to those with the −308 GG genotype.Conclusion.TNF-α −308 GA/AA genotypes were found to be related to higher inflammatory activity and worse measures of disease activity in Portuguese patients with JIA. They were not associated with susceptibility to JIA.

Sign in / Sign up

Export Citation Format

Share Document