title: The protective role of the transmembrane thioredoxin-related protein TMX in inflammatory liver injury.
abstract: OBJECTIVE
  Accumulating evidence indicates that oxidative stress is associated with inflammation, and the cellular redox status can determine the sensitivity and the final outcome in response to inflammatory stimuli. To control the redox balance, mammalian cells contain a variety of oxidoreductases belonging to the thioredoxin superfamily. The large number of these enzymes suggests a complex mechanism of redox regulation in mammals, but the precise function of each family member awaits further investigations.
  
  
  RESULTS
  We generated mice deficient in transmembrane thioredoxin-related protein (TMX), a transmembrane oxidoreductase in the endoplasmic reticulum (ER). When exposed to lipopolysaccharide (LPS) and d-(+)-galactosamine (GalN) to induce inflammatory liver injury, mutant mice were highly susceptible to the toxicants and developed severe liver damage. LPS-induced production of inflammatory mediators was equivalent in both wild-type and TMX(-/-) mice, whereas neutralization of the proinflammatory cytokine tumor necrosis factor-α suppressed the toxic effects of LPS/GalN in the mutant mice. Liver transcriptional profiles revealed enhanced activation of the p53-signaling pathway in the TMX(-/-) mice after LPS/GalN treatment. Furthermore, TMX deficiency also caused increased sensitivity to thioacetamide, which exerts its hepatotoxicity through the generation of reactive oxygen species.
  
  
  METHODS
  The present study is the first to address the role of the oxidoreductase TMX in inflammatory liver injury. The phenotype of mice deficient in TMX suggests a functional link between redox regulation in the ER and susceptibility to oxidative tissue damage.
  
  
  CONCLUSIONS
  We conclude that TMX plays a major role in host defense under the type of inflammatory conditions associated with oxidative stress.
authors.affiliation: Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Kana
authors.initials: K
authors.lastname: Irie
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okuyama
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Aoi
authors.initials: A
authors.lastname: Son
authors.forename: Dorys Adriana
authors.initials: DA
authors.lastname: Lopez-Ramos
authors.forename: Hai
authors.initials: H
authors.lastname: Tian
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Oka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.forename: Shinae
authors.initials: S
authors.lastname: Kizaka-Kondoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masutani
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D005688:Galactosamine / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006505:Hepatitis / Q000235:genetics* / Q000276:immunology; D006720:Homozygote; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D005688:Galactosamine; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010088:Oxidoreductases; D013879:Thioredoxins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C582883:TMX protein, mouse