I. Bohlinger et al., INTERLEUKIN-1 AND NITRIC-OXIDE PROTECT AGAINST TUMOR-NECROSIS-FACTOR ALPHA-INDUCED LIVER-INJURY THROUGH DISTINCT PATHWAYS, Hepatology, 22(6), 1995, pp. 1829-1837
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.