Involvement of a serine protease, but not of neutrophil elastase, in tumor necrosis factor-induced lethal hepatitis and induction of platelet-activating factor

Ben Wielockx, Federico Bussolino, Steven D. Shapiro, Claude Libert

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)490-497
Number of pages8
JournalJournal of Hepatology
Volume35
Issue number4
DOIs
Publication statusPublished - 2001

Fingerprint

Leukocyte Elastase
Platelet Activating Factor
Serine Proteases
Hepatitis
Tumor Necrosis Factor-alpha
Trypsin Inhibitors
Soybeans
Galactosamine
Gene Targeting
Pancreatic Elastase
Chronic Hepatitis
Peptide Hydrolases

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 journalArticle

@article{533a9244609a4d3184e2109cb4c0c9c5,
title = "Involvement of a serine protease, but not of neutrophil elastase, in tumor necrosis factor-induced lethal hepatitis and induction of platelet-activating factor",
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.",
keywords = "Hepatitis, Neutrophils, Serine protease inhibitors, Tumor necrosis factor",
author = "Ben Wielockx and Federico Bussolino and Shapiro, {Steven D.} and Claude Libert",
year = "2001",
doi = "10.1016/S0168-8278(01)00150-7",
language = "English",
volume = "35",
pages = "490--497",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier B.V.",
number = "4",

}

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 -