TOLERANCE AGAINST TUMOR-NECROSIS-FACTOR ALPHA(TNF)-INDUCED HEPATOTOXICITY IN MICE - THE ROLE OF NITRIC-OXIDE

D-Galactosamine-sensitized mice challenged with tumor necrosis factor alpha (TNF) developed severe apoptotic and secondary necrotic liver in jury as assessed by histology, measurement of cytosolic DNA fragments and determination of liver-specific enzymes in plasma. Pretreatment of mice with interleukin-1 beta (IL-1) resulted in elevated levels of ni trite/nitrate in serum and rendered mice insensitive towards TNF toxic ity. Pharmacological doses of the nitric oxide (NO) donor sodium nitro prusside (SNP) also conferred complete protection against TNF toxicity , suggesting a possible link between IL-1- and NO-induced protection. However? NO-synthesis inhibition by N-G-monomethyl-L-arginine failed t o abrogate IL-l-induced tolerance against TNF toxicity. We conclude th at IL-1 and NO protect against TNF-induced liver injury through distin ct pathways.