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Interleukin‐1 and nitric oxide protect against tumor necrosis factor α‐induced liver injury through distinct pathways

Mice sensitized with D‐galactosamine (GalN) and challenged with recombinant murine tumor necrosis factor α (TNFα) developed severe apoptotic and secondary necrotic liver injury as assessed by histology, measurement of cytosolic DNA fragments, and determination of liver specific enzymes in plasma. Pretreatment with recombinant human interleukin‐1β (IL‐1) rendered mice insensitive to this TNFα toxicity. Coadministration of the liver‐specific transcriptional inhibitor GalN with IL‐1 prevented the development of tolerance, implicating de novo synthesis of liver specific proteins in the induction of tolerance. Pretreatment of mice with IL‐1 resulted in elevated levels of nitrite/nitrate in serum and in enhanced nitric oxide synthase (NOS) activity in liver cells isolated from these animals. In addition, pharmacological doses of the nitric oxide (NO) donor sodium nitroprusside conferred complete protection against TNFα‐induced liver injury in galactosamine‐sensitized mice, suggesting a possible link between IL‐1‐ and NO‐in‐duced protection. However, prevention of NO‐synthesis by NG‐monomethyl‐L‐arginine (NMMA) did not abolish IL‐1‐induced tolerance to TNFα in vivo. Cytotoxicity of TNFα to isolated hepatocytes sensitized with actinomycin D (ActD) was not significantly altered by inhibition of endogenous nitrite release. Also, enhanced NO production elicited in vitro by glycerol trinitrate or ex vivo by pretreatment with IL‐1 had no significant effect in this system. We conclude that IL‐1‐ and NO‐induced protection of mice against TNFα‐mediated liver damage follow distinct pathways. (Hepatology 1995; 22:1829‐1837).