Tumor necrosis factor-alpha induces activation of coagulation and fibrinolysis in baboons through an exclusive effect on the p55 receptor.
Tumor necrosis factor-alpha (TNF-alpha) can bind to two distinct transmembrane receptors, the p55 and p75 TNF receptors. We compared the capability of two mutant TNF proteins with exclusive affinity for the p55 or p75 TNF receptor with that of wild type TNF, to activate the hemostatic mechanism in baboons. Both activation of the coagulation system, monitored by the plasma levels of thrombin-antithrombin III complexes, and activation of the fibrinolytic system (plasma levels of tissue-type plasminogen activator, and plasminogen activator inhibitor type I), were of similar magnitude after intravenous injection of wild type TNF or the TNF mutant with affinity only for the p55 receptor. Likewise, wild type TNF and the TNF p55 specific mutant were equally potent in inducing neutrophil degranulation (plasma levels of elastase-alpha 1-antitrypsin complexes). Wild type TNF tended to be a more potent inducer of secretory phospholipase A2 release than the p55 specific TNF mutant. Administration of the TNF mutant binding only to the p75 receptor did not induce any of these responses. We conclude that TNF-Induced stimulation of coagulation, fibrinolysis, neutrophil degranulation, and release of secretory phospholipase A2 are predominantly mediated by the p55 TNF receptor.
van der Poll
T
T
Cornell University Medical College, Laboratory of Surgical Metabolism, New York, NY 10021, USA.
Jansen
P M
PM
Van Zee
K J
KJ
Welborn
M B
MB
de Jong
I
I
Hack
C E
CE
Loetscher
H
H
Lesslauer
W
W
Lowry
S F
SF
Moldawer
L L
LL
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects* / Q000502:physiology; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology; D019272:Leukocyte Elastase; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism; D010215:Papio / Q000097:blood; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D017354:Point Mutation; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins / Q000494:pharmacology; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D010741:Phospholipases A; D054467:Phospholipases A2; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase