Mechanism of NFκB activation by interleukin-1 and tumour necrosis factor in endothelial cells

1996 ◽  
Vol 24 (1) ◽  
pp. 2S-2S ◽  
Author(s):  
Andrew Bowie ◽  
Paul N. Moynagh ◽  
Luke A.J. O'neill
Keyword(s):  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Interleukin 1 ◽  
Necrosis Factor

scholarly journals Interleukin-1, Tumour Necrosis Factor and Treatment of the Septic Shock Syndrome

1992 ◽  
Vol 3 (suppl b) ◽  
pp. 11-19
Author(s):  
Charles A Dinarello
Keyword(s):  
Septic Shock ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Neutralizing Antibodies ◽  
Inflammatory Diseases ◽  
Leukocyte Adhesion ◽  
Interleukin 1 ◽  
Platelet Activating Factor ◽  
Surface Receptors ◽  
Necrosis Factor

Treating the septic shock syndrome with antibodies that block only endotoxin has its limitations. Other targets for treating septic shock include neutralizing antibodies to the complement fragment C5a, platelet activating factor antagonists and blockade of endothelial cell leukocyte adhesion molecules. Specific blockade of the pro-inflammatory cytokines interleukin-1 (IL-1) or tumour necrosis factor (TNF) reduces the morbidity and mortality associated with septic shock. Moreover, blocking IL-1 and TNF likely has uses in treating diseases other than septic shock. Use of neutralizing antibodies to TNF or IL-1 receptors has reduced the consequences of infection and inflammation, including lethal outcomes in animal models. The IL-1 receptor antagonist, a naturally occurring cytokine, blocks shock and death due to Escherichia coli as well as ameliorates a variety of inflammatory diseases. Soluble TNF and IL-1 surface receptors, which bind their respective cytokines. also ameliorate disease processes. Clinical trials are presently evaluating the safety and efficacy of anticytokine therapies either alone or in combination.

scholarly journals Heterogeneous regulation of constitutive thrombomodulin or inducible tissue-factor activities on the surface of human saphenous-vein endothelial cells in culture following stimulation by interleukin-1, tumour necrosis factor, thrombin or phorbol ester

1991 ◽  
Vol 273 (3) ◽  
pp. 679-684 ◽  
Author(s):  
G Archipoff ◽  
A Beretz ◽  
J M Freyssinet ◽  
C Klein-Soyer ◽  
C Brisson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Saphenous Vein ◽  
Tumour Necrosis ◽  
Protein C ◽  
Interleukin 1 ◽  
Factor Activity ◽  
Human Saphenous Vein ◽  
Tissue Factor Activity ◽  
Necrosis Factor

Thrombomodulin and tissue-factor activities were measured on the surface of confluent human saphenous-vein endothelial cells (HSVEC) cultivated in 96-multiwell plates. Thrombomodulin activity was measured in the presence of purified human thrombin (2.2 nM) and protein C (65 nM). Tissue-factor activity was measured with purified human Factor VII (5 nM) and Factor X (400 nM). Generated activated protein C and Factor Xa released in the supernatant were assayed with chromogenic substrates. Resting cells exhibited significant thrombomodulin activity, but no detectable tissue-factor activity. After 4 h of preincubation with tumour necrosis factor (TNF, 22-2200 pM), interleukin-1 (IL-1, 5.7-570 nM) or phorbol myristate acetate (PMA, 1.61-161 nM) there was an increase in tissue-factor activity and a concomitant decrease in thrombomodulin activity. However, the extent of both responses varied according to the nature of the stimulus. Thrombin (0.44-44 nM) also induced an increase in tissue-factor activity, but had no effect on thrombomodulin activity. Kinetic studies showed that for all stimuli the increase in tissue factor was transient, reaching a maximum after 4-8 h of preincubation with the stimulating agent and returning to normal values after 24 h. IL-1 and TNF induced a time-dependent decrease in thrombomodulin, by respectively 47% and 67% of control values after 24 h. However, PMA induced only a transient down-regulation of thrombomodulin, full activity being recovered after 18 h. Hence this simultaneous assay system, using intact HSVEC and purified human coagulation factors, enabled us to observe that the regulation of thrombin generation could be diversely affected by various substances known to stimulate the endothelium. This suggests that the simultaneous and opposite modulation of these proteins does not represent an unified response of the endothelial cells to procoagulant stimuli. These results also confirm the absence of effect of thrombin on the expression of thrombomodulin on the cell surface.

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