Involvement of a serine protease, but not of neutrophil elastase, in tumor necrosis factor-induced lethal hepatitis and induction of platelet-activating factor.
OBJECTIVE
Tumor necrosis factor (TNF) plays an essential role in several types of acute and chronic hepatitis. Our aims in the present study were to elucidate the mechanism by which TNF leads to acute lethal hepatitis, thereby focusing on the role of serine proteases and platelet-activating factor (PAF).


METHODS
All experiments were performed in a model of acute hepatitis, induced by TNF in combination with D-(+)-galactosamine (GalN). Neutrophil elastase (NE)-deficient mice, generated by gene targeting were used in the studies.


RESULTS
We found that a serine protease plays an essential mediating role in the in vivo TNF effect as alpha1-antitrypsin (alpha1-AT), soybean trypsin inhibitor (STI) and turkey trypsin inhibitor (TTI), confer complete protection. alpha1-AT and TTI, but not STI, reduce PAF blood levels, induced by TNF/GalN, which is compatible with an elastase-like serine protease involvement in PAF synthesis. In our search for relevant serine proteases we believed that NE was an excellent candidate protease. However, we found that TNF/GalN-induced lethality is not attenuated in mice deficient in NE.


CONCLUSIONS
The data suggest that TNF-induced lethal hepatitis is accompanied by increases in circulating PAF and plasma clotting time, and mediated by a serine protease, but not by NE.
Wielockx
B
B
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Belgium.
Bussolino
F
F
Shapiro
S D
SD
Libert
C
C
D000208:Acute Disease; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000401:mortality*; D004338:Drug Combinations; D005688:Galactosamine; D019272:Leukocyte Elastase / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010972:Platelet Activating Factor / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha
D004338:Drug Combinations; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D012697:Serine Endopeptidases; D019272:Leukocyte Elastase