Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice.
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Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice. / Sass, G; Koerber, K; Bang, R; Guehring, H; Tiegs, Gisa.
in: J CLIN INVEST, Jahrgang 107, Nr. 4, 4, 2001, S. 439-447.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice.
AU - Sass, G
AU - Koerber, K
AU - Bang, R
AU - Guehring, H
AU - Tiegs, Gisa
PY - 2001
Y1 - 2001
N2 - Concanavalin A (Con A) causes severe TNF-alpha-mediated and IFN-gamma-mediated liver injury in mice. In addition to their other functions, TNF-alpha and IFN-gamma both induce the inducible nitric oxide (NO) synthase (iNOS). Using different models of liver injury, NO was found to either mediate or prevent liver damage. To further elucidate the relevance of NO for liver damage we investigated the role of iNOS-derived NO in the Con A model. We report that iNOS mRNA was induced in livers of Con A-treated mice within 2 hours, with iNOS protein becoming detectable in hepatocytes as well as in Kupffer cells within 4 hours. iNOS-/- mice were protected from liver damage after Con A treatment, as well as in another TNF-alpha-mediated model that is inducible by LPS in D-galactosamine-sensitized (GalN-sensitized) mice. iNOS-deficient mice were not protected after direct administration of recombinant TNF-alpha to GalN-treated mice. Accordingly, pretreatment of wild-type mice with a potent and specific inhibitor of iNOS significantly reduced transaminase release after Con A or GalN/LPS, but not after GalN/TNF-alpha treatment. Furthermore, the amount of plasma TNF-alpha and of intrahepatic TNF-alpha mRNA and protein was significantly reduced in iNOS-/- mice. Our results demonstrate that iNOS-derived NO regulates proinflammatory genes in vivo, thereby contributing to inflammatory liver injury in mice by stimulation of TNF-alpha production.
AB - Concanavalin A (Con A) causes severe TNF-alpha-mediated and IFN-gamma-mediated liver injury in mice. In addition to their other functions, TNF-alpha and IFN-gamma both induce the inducible nitric oxide (NO) synthase (iNOS). Using different models of liver injury, NO was found to either mediate or prevent liver damage. To further elucidate the relevance of NO for liver damage we investigated the role of iNOS-derived NO in the Con A model. We report that iNOS mRNA was induced in livers of Con A-treated mice within 2 hours, with iNOS protein becoming detectable in hepatocytes as well as in Kupffer cells within 4 hours. iNOS-/- mice were protected from liver damage after Con A treatment, as well as in another TNF-alpha-mediated model that is inducible by LPS in D-galactosamine-sensitized (GalN-sensitized) mice. iNOS-deficient mice were not protected after direct administration of recombinant TNF-alpha to GalN-treated mice. Accordingly, pretreatment of wild-type mice with a potent and specific inhibitor of iNOS significantly reduced transaminase release after Con A or GalN/LPS, but not after GalN/TNF-alpha treatment. Furthermore, the amount of plasma TNF-alpha and of intrahepatic TNF-alpha mRNA and protein was significantly reduced in iNOS-/- mice. Our results demonstrate that iNOS-derived NO regulates proinflammatory genes in vivo, thereby contributing to inflammatory liver injury in mice by stimulation of TNF-alpha production.
KW - Animals
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Interferon-gamma/biosynthesis
KW - Concanavalin A/toxicity
KW - Tumor Necrosis Factor-alpha/biosynthesis
KW - Nitric Oxide Synthase Type II
KW - Nitric Oxide Synthase/physiology
KW - Liver/enzymology/pathology
KW - Lysine/analogs & derivatives/pharmacology
KW - Animals
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Interferon-gamma/biosynthesis
KW - Concanavalin A/toxicity
KW - Tumor Necrosis Factor-alpha/biosynthesis
KW - Nitric Oxide Synthase Type II
KW - Nitric Oxide Synthase/physiology
KW - Liver/enzymology/pathology
KW - Lysine/analogs & derivatives/pharmacology
M3 - SCORING: Journal article
VL - 107
SP - 439
EP - 447
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 4
M1 - 4
ER -