Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice.

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.

[1]  H. Bergmeyer.  Methods of Enzymatic Analysis , 2019 .

[2]  T. Papadopoulos,et al.  Importance of Kupffer cells for T-cell-dependent liver injury in mice. , 2000, The American journal of pathology.

[3]  G. Tiegs,et al.  Synergism of Pseudomonas aeruginosa exotoxin A with endotoxin, superantigen, or TNF results in TNFR1- and TNFR2-dependent liver toxicity in mice. , 2000, Immunology letters.

[4]  Mao-tsun Lin,et al.  Staphylococcal Enterotoxin A Acts through Nitric Oxide Synthase Mechanisms in Human Peripheral Blood Mononuclear Cells To Stimulate Synthesis of Pyrogenic Cytokines , 2000, Infection and Immunity.

[5]  C. García-Monzón,et al.  Intrahepatic accumulation of nitrotyrosine in chronic viral hepatitis is associated with histological severity of liver disease. , 2000, Journal of hepatology.

[6]  G. Tiegs,et al.  Pathophysiological mechanisms of TNF during intoxication with natural or man-made toxins. , 1999, Toxicology.

[7]  M. Nagayama,et al.  Beneficial effects of inducible nitric oxide synthase inhibitor on reperfusion injury in the pig liver. , 1999, Transplantation.

[8]  Simon C Watkins,et al.  A novel nitric oxide scavenger decreases liver injury and improves survival after hemorrhagic shock. , 1999, The American journal of physiology.

[9]  S. Seki,et al.  Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis. , 1999, Journal of hepatology.

[10]  I. Mcfarlane.  Pathogenesis of autoimmune hepatitis. , 1999, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[11]  T. Billiar,et al.  IV. Determinants of nitric oxide protection and toxicity in liver. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[12]  M. Wheeler,et al.  An E-box within the MHC IIB gene is bound by MyoD and is required for gene expression in fast muscle. , 1999, American journal of physiology. Cell physiology.

[13]  H. Mühl,et al.  Inducible NO synthase: role in cellular signalling. , 1999, The Journal of experimental biology.

[14]  Y. Yamaguchi,et al.  Peroxynitrite formation during rat hepatic allograft rejection , 1999, Hepatology.

[15]  N. Koide,et al.  Role of Nitric Oxide in Lipopolysaccharide-Induced Hepatic Injury in d-Galactosamine-Sensitized Mice as an Experimental Endotoxic Shock Model , 1999, Infection and Immunity.

[16]  M. Lohoff,et al.  Acute hepatotoxicity of Pseudomonas aeruginosa exotoxin A in mice depends on T cells and TNF. , 1998, Journal of immunology.

[17]  C. Lowenstein,et al.  Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  T. Billiar,et al.  Nitric Oxide Prevents IL-1β and IFN-γ-Inducing Factor (IL-18) Release from Macrophages by Inhibiting Caspase-1 (IL-1β-Converting Enzyme) , 1998, The Journal of Immunology.

[19]  P. Muriel.  Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride. , 1998, Biochemical pharmacology.

[20]  Simon C Watkins,et al.  Interleukin-6 production in hemorrhagic shock is accompanied by neutrophil recruitment and lung injury. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[21]  T. Billiar,et al.  Adenovirus-mediated inducible nitric oxide synthase gene transfer inhibits hepatocyte apoptosis. , 1998, Surgery.

[22]  T. Billiar,et al.  Inducible nitric oxide synthase in the liver: regulation and function. , 1998, Biochemistry. Biokhimiia.

[23]  L. Moldawer,et al.  Disparate Roles for TNF-α and Fas Ligand in Concanavalin A-Induced Hepatitis , 1998, The Journal of Immunology.

[24]  A. Peitzman,et al.  Essential Role of Induced Nitric Oxide in the Initiation of the Inflammatory Response after Hemorrhagic Shock , 1998, The Journal of experimental medicine.

[25]  Carl Nathan.  Inducible nitric oxide synthase: what difference does it make? , 1997, The Journal of clinical investigation.

[26]  T. Michel,et al.  Nitric oxide synthases: which, where, how, and why? , 1997, The Journal of clinical investigation.

[27]  George Kollias,et al.  In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis , 1997, European journal of immunology.

[28]  D. Harrison,et al.  Cellular and molecular mechanisms of endothelial cell dysfunction. , 1997, The Journal of clinical investigation.

[29]  B. Halliwell.  What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo? , 1997, FEBS letters.

[30]  Simon C Watkins,et al.  Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. , 1997, Journal of medicinal chemistry.

[31]  F. Fang.  Mechanisms of nitric oxide-related antimicrobial activity , 1997 .

[32]  F. Fang.  Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. , 1997, The Journal of clinical investigation.

[33]  Simon C Watkins,et al.  Nitric Oxide Protects Cultured Rat Hepatocytes from Tumor Necrosis Factor-α-induced Apoptosis by Inducing Heat Shock Protein 70 Expression* , 1997, The Journal of Biological Chemistry.

[34]  J. Vauthey,et al.  Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor. , 1997, Journal of immunology.

[35]  J S Beckman,et al.  Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. , 1996, The American journal of physiology.

[36]  S. Küsters,et al.  Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. , 1996, Gastroenterology.

[37]  H. Fujiwara,et al.  Critical involvement of interferon γ in the pathogenesis of T‐cell activation‐associated hepatitis and regulatory mechanisms of interleukin‐6 for the manifestations of hepatitis , 1996, Hepatology.

[38]  M. Leist,et al.  Interleukin‐1 and nitric oxide protect against tumor necrosis factor α‐induced liver injury through distinct pathways , 1995, Hepatology.

[39]  C. Thiemermann,et al.  The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase , 1995, British journal of pharmacology.

[40]  J. Stamler,et al.  Nitric oxide production in experimental alcoholic liver disease in the rat: role in protection from injury. , 1995, Gastroenterology.

[41]  M. Currie,et al.  Dual inhibition of nitric oxide and prostaglandin production contributes to the antiinflammatory properties of nitric oxide synthase inhibitors. , 1995, The Journal of clinical investigation.

[42]  C. Nathan,et al.  Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase , 1995, Cell.

[43]  S. Endres,et al.  Exogenous and endogenous nitric oxide attenuates tumor necrosis factor synthesis in the murine macrophage cell line RAW 264.7. , 1995, Journal of immunology.

[44]  T. Billiar,et al.  Cyclic GMP and guanylate cyclase mediate lipopolysaccharide‐induced Kupffer cell tumor necrosis factor‐α synthesis , 1995, Journal of leukocyte biology.

[45]  J. Pfeilschifter,et al.  Dexamethasone differentially affects interleukin 1 beta- and cyclic AMP-induced nitric oxide synthase mRNA expression in renal mesangial cells. , 1994, The Biochemical journal.

[46]  M. Currie,et al.  L-N6-(1-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. , 1994, Journal of medicinal chemistry.

[47]  E. O’Neill,et al.  T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6 , 1994, The Journal of experimental medicine.

[48]  B. Ryffel,et al.  Interferon gamma receptor deficient mice are resistant to endotoxic shock , 1994, The Journal of experimental medicine.

[49]  S. Endres,et al.  Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells. , 1993, Biochemical and biophysical research communications.

[50]  A. Nussler,et al.  Inflammation, immunoregulation, and inducible nitric oxide synthase , 1993, Journal of leukocyte biology.

[51]  C. Tannenbaum,et al.  Synergistic cooperation between T cell lymphokines for induction of the nitric oxide synthase gene in murine peritoneal macrophages. , 1993, Journal of immunology.

[52]  B. Barton,et al.  Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model , 1993, Infection and immunity.

[53]  A. Wendel,et al.  A T cell-dependent experimental liver injury in mice inducible by concanavalin A. , 1992, The Journal of clinical investigation.

[54]  T. Billiar,et al.  Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. , 1990, Annals of surgery.

[55]  C. Galanos,et al.  Requirement for lipopolysaccharide-responsive macrophages in galactosamine-induced sensitization to endotoxin , 1986, Infection and immunity.

[56]  M J Koziel,et al.  Cytokines in Viral Hepatitis , 1999, Seminars in liver disease.

[57]  C. Nathan,et al.  Nitric oxide and macrophage function. , 1997, Annual review of immunology.

[58]  A. Wendel,et al.  Protection from T cell-mediated murine liver failure by phosphodiesterase inhibitors. , 1997, The Journal of pharmacology and experimental therapeutics.

[59]  M. Leist,et al.  Concanavalin A - induced T-cell - mediated hepatic injury in mice : The role of tumor necrosis factor , 1995 .