In vivo evidence for protease-catalysed mechanism providing bioactive tumor necrosis factor alpha.
Mice pretreated by intravenous injection of 42 mg/kg of the serine protease inhibitor alpha 1-antitrypsin prior to a hepatotoxic dose of D-galactosamine/lipopolysaccharide (GalN/LPS) were fully protected against hepatitis. Pretreatment with alpha 1-antitrypsin with doses up to 300 mg/kg at different times failed to protect galactosamine sensitized animals against tumor necrosis factor alpha (TNF alpha)-induced hepatitis. No bioactive TNF alpha was detectable in serum of mice protected against GalN/LPS-induced hepatitis by pretreatment with alpha 1-antitrypsin. In contrast, abundant amounts of TNF were found in sera of GalN/LPS-treated control animals. It is concluded that a serine protease sensitive to alpha 1-antitrypsin provides bioactive TNF alpha by proteolytic cleavage of a TNF alpha precursor.
Niehörster
M
M
Faculty of Biology, University of Konstanz, Federal Republic of Germany.
Tiegs
G
G
Schade
U F
UF
Wendel
A
A
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005688:Galactosamine / Q000633:toxicity; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008954:Models, Biological; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000633:toxicity; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D005688:Galactosamine; D000410:Alanine Transaminase; D012697:Serine Endopeptidases