title: A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure.
abstract: BACKGROUND
  Acute liver failure (ALF) can be induced in mice by administering Escherichia coli lipopolysaccharide (LPS) and D-galactosamine (D-GalN), which induce an inflammatory response involving tumour necrosis factor (TNF)-α production and a hepatocyte-specific transcriptional block. Under these conditions, binding of TNF-α to its cognate receptor on hepatocytes eventually leads to their apoptosis.
  
  
  OBJECTIVE
  As part of an effort to identify drugs to treat this disease model, we have investigated whether the glutamine synthetase inhibitor methionine sulfoximine (MSO) could play a protective role, given its effectiveness in the inhibition of brain swelling associated with hyperammonaemia.
  
  
  METHODS
  Mouse survival, glutamine synthetase activity, hepatocyte apoptosis and induction of inflammatory cytokines were measured in mice treated with MSO before an intraperitoneal injection of LPS/D-GalN. The effect of MSO on viability and on TNF-α release was also assessed on inflammatory and liver cells.
  
  
  RESULTS
  We have found that, in mice treated with LPS/D-GalN, MSO (i) drastically increases animal survival; (ii) sharply reduces glutamine synthetase activity, without inhibiting its other target, γ-glutamyl cysteine synthetase; (iii) inhibits death receptor-mediated apoptosis in hepatocytes upstream to cytokine binding; (iv) strongly reduces the overall inflammatory cytokine response, including a significant decrease in TNF-α induction in vivo and ex vivo, and in the interferon-γ level and signalling.
  
  
  CONCLUSIONS
  These results demonstrate that the MSO target glutamine synthetase is required for the early steps of the cytokine response to endotoxins, and that its pharmacological inhibition may be exploited to treat inflammation.
authors: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors: Amruta A
authors: AA
authors: Jambekar
authors: Elena
authors: E
authors: Palma
authors: Luca
authors: L
authors: Nicolosi
authors: Andrea
authors: A
authors: Rasola
authors: Valeria
authors: V
authors: Petronilli
authors: Federica
authors: F
authors: Chiara
authors: Paolo
authors: P
authors: Bernardi
authors: Richard
authors: R
authors: Needleman
authors: William S A
authors: WS
authors: Brusilow
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005688:Galactosamine; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D008717:Methionine Sulfoximine; D005688:Galactosamine; D007371:Interferon-gamma; D005974:Glutamate-Ammonia Ligase