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.