INTERLEUKIN-1 AND NITRIC-OXIDE PROTECT AGAINST TUMOR-NECROSIS-FACTOR ALPHA-INDUCED LIVER-INJURY THROUGH DISTINCT PATHWAYS

Mice sensitized with D-galactosamine (GalN) and challenged with recomb inant murine tumor necrosis factor alpha (TNF alpha) developed severe apoptotic and secondary necrotic liver injury as assessed by histology , measurement of cytosolic DNA fragments, and determination of liver s pecific enzymes in plasma. Pretreatment with recombinant human interle ukin-lp (H-l) rendered mice insensitive to this TNF alpha toxicity. Co administration of the Liver-specific transcriptional inhibitor GalN wi th IL-1 prevented the development of tolerance, implicating de novo sy nthesis of liver specific proteins in the induction of tolerance, Pret reatment of mice with IL-1 resulted in elevated levels of nitrite/nitr ate in serum and in enhanced nitric oxide synthase (NOS) activity in l iver cells isolated from these animals, In addition, pharmacological d oses of the nitric oxide (NO) donor sodium nitroprusside conferred com plete protection against TNF alpha-induced liver injury in galactosami ne-sensitized mice, suggesting a possible link between IL-1- and NO-in duced protection, However, prevention of NO-synthesis by N-G-monomethy l-L-arginine (NMMA) did not abolish IL-l-induced tolerance to TNF alph a in vivo. Cytotoxicity of TNF alpha to isolated hepatocytes sensitize d with actinomycin D (ActD) was not significantly altered by inhibitio n of endogenous nitrite release, Also, enhanced NO production elicited in vitro by glycerol trinitrate or ex vivo by pretreatment with IL-l had no significant effect in this system. We conclude that IL-1- and N O-induced protection of mice against TNF alpha-mediated Liver damage f ollow distinct pathways.