Abstract
Background/Aims: 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 α1-antitrypsin (α1-AT), soybean trypsin inhibitor (STI) and turkey trypsin inhibitor (TTI), confer complete protection, α1-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.
| Original language | English |
|---|---|
| Pages (from-to) | 490-497 |
| Number of pages | 8 |
| Journal | Journal of Hepatology |
| Volume | 35 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2001 |
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Keywords
- Hepatitis
- Neutrophils
- Serine protease inhibitors
- Tumor necrosis factor
ASJC Scopus subject areas
- Gastroenterology
Cite this
Involvement of a serine protease, but not of neutrophil elastase, in tumor necrosis factor-induced lethal hepatitis and induction of platelet-activating factor. / Wielockx, Ben; Bussolino, Federico; Shapiro, Steven D.; Libert, Claude.
In: Journal of Hepatology, Vol. 35, No. 4, 2001, p. 490-497.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Involvement of a serine protease, but not of neutrophil elastase, in tumor necrosis factor-induced lethal hepatitis and induction of platelet-activating factor
AU - Wielockx, Ben
AU - Bussolino, Federico
AU - Shapiro, Steven D.
AU - Libert, Claude
PY - 2001
Y1 - 2001
N2 - Background/Aims: 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 α1-antitrypsin (α1-AT), soybean trypsin inhibitor (STI) and turkey trypsin inhibitor (TTI), confer complete protection, α1-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.
AB - Background/Aims: 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 α1-antitrypsin (α1-AT), soybean trypsin inhibitor (STI) and turkey trypsin inhibitor (TTI), confer complete protection, α1-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.
KW - Hepatitis
KW - Neutrophils
KW - Serine protease inhibitors
KW - Tumor necrosis factor
UR - http://www.scopus.com/inward/record.url?scp=0034788260&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034788260&partnerID=8YFLogxK
U2 - 10.1016/S0168-8278(01)00150-7
DO - 10.1016/S0168-8278(01)00150-7
M3 - Article
C2 - 11682033
AN - SCOPUS:0034788260
VL - 35
SP - 490
EP - 497
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 4
ER -