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The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-α

1992; Lippincott Williams & Wilkins; Volume: 15; Issue: 1 Linguagem: Inglês

10.1002/hep.1840150121

1527-3350

Joseph Alcorn, Joshua Fierer, Mario Chojkier,

Immune Cell Function and Interaction

D-Galactosamine is an hepatocyte-specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide-induced mediator of shock, tumor necrosis factor-α. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute-phase proteins, we postulated that the lipopolysaccharide-sensitizing effect of D-galactosamine could be caused by its inhibition of acute-phase product transcription. We confirmed that the acute-phase response to lipopolysaccharide was attenuated by simultaneous administration of D-galactosamine. However, when the acute-phase response was induced by subcutaneous turpentine 24 hr before D-galactosamine administration, the effect of D-galactosamine on circulating acute-phase reactants was negligible. Furthermore, induction of an a priori acute-phase response protected mice from both D-galactosamine/lipopolysaccharide and D-galactosamine/tumor necrosis factor-α-induced death. The turpentine-induced acute-phase response did not decrease endogenous tumor necrosis factor-α production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor-α. Thus we suggest that the acute-phase response protects against death in D-galactosamine—sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor-α release. (Hepatology 1992;15:122-129).