Interleukin-1 and nitric oxide protect against tumor necrosis factor alpha-induced liver injury through distinct pathways.
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Interleukin-1 and nitric oxide protect against tumor necrosis factor alpha-induced liver injury through distinct pathways. / Bohlinger, I; Leist, M; Barsig, J; Uhlig, S; Tiegs, Gisa; Wendel, A.
In: HEPATOLOGY, Vol. 22, No. 6, 6, 1995, p. 1829-1837.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Interleukin-1 and nitric oxide protect against tumor necrosis factor alpha-induced liver injury through distinct pathways.
AU - Bohlinger, I
AU - Leist, M
AU - Barsig, J
AU - Uhlig, S
AU - Tiegs, Gisa
AU - Wendel, A
PY - 1995
Y1 - 1995
N2 - Mice sensitized with D-galactosamine (GalN) and challenged with recombinant 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 specific enzymes in plasma. Pretreatment with recombinant human interleukin-1 beta (IL-1) rendered mice insensitive to this TNF alpha 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 TNF alpha-induced liver injury in galactosamine-sensitized mice, suggesting a possible link between IL-1- and NO-induced protection. However, prevention of NO-synthesis by NG-monomethyl-L-arginine (NMMA) did not abolish IL-1-induced tolerance to TNF alpha in vivo. Cytotoxicity of TNF alpha 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 TNF alpha-mediated liver damage follow distinct pathways.
AB - Mice sensitized with D-galactosamine (GalN) and challenged with recombinant 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 specific enzymes in plasma. Pretreatment with recombinant human interleukin-1 beta (IL-1) rendered mice insensitive to this TNF alpha 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 TNF alpha-induced liver injury in galactosamine-sensitized mice, suggesting a possible link between IL-1- and NO-induced protection. However, prevention of NO-synthesis by NG-monomethyl-L-arginine (NMMA) did not abolish IL-1-induced tolerance to TNF alpha in vivo. Cytotoxicity of TNF alpha 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 TNF alpha-mediated liver damage follow distinct pathways.
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Drug Tolerance
KW - Recombinant Proteins
KW - Drug-Induced Liver Injury
KW - Galactosamine/pharmacology
KW - DNA/metabolism
KW - Nitroprusside/pharmacology
KW - Tumor Necrosis Factor-alpha/toxicity
KW - Interleukin-1/pharmacology
KW - Liver/enzymology/pathology
KW - Liver Diseases/pathology/prevention & control
KW - Necrosis/chemically induced
KW - Nitrates/blood
KW - Nitric Oxide/metabolism/pharmacology
KW - Nitric Oxide Synthase/metabolism
KW - Nitrites/blood
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Drug Tolerance
KW - Recombinant Proteins
KW - Drug-Induced Liver Injury
KW - Galactosamine/pharmacology
KW - DNA/metabolism
KW - Nitroprusside/pharmacology
KW - Tumor Necrosis Factor-alpha/toxicity
KW - Interleukin-1/pharmacology
KW - Liver/enzymology/pathology
KW - Liver Diseases/pathology/prevention & control
KW - Necrosis/chemically induced
KW - Nitrates/blood
KW - Nitric Oxide/metabolism/pharmacology
KW - Nitric Oxide Synthase/metabolism
KW - Nitrites/blood
M3 - SCORING: Journal article
VL - 22
SP - 1829
EP - 1837
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 6
M1 - 6
ER -
