title: Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.
abstract: OBJECTIVE
  The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys) and secrete substantial amounts of L-Glutamate (L-Glu) via the transport system Xc- (4F2hc+xCT), and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes.
  
  
  METHODS
  We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM), and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha.
  
  
  RESULTS
  The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19), the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio.
  
  
  CONCLUSIONS
  A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kakazu
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Kondo
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Masashi
authors.initials: M
authors.lastname: Ninomiya
authors.forename: Osamu
authors.initials: O
authors.lastname: Kimura
authors.forename: Yuta
authors.initials: Y
authors.lastname: Wakui
authors.forename: Koji
authors.initials: K
authors.lastname: Fukushima
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamai
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D027182:Amino Acid Transport System y+ / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003553:Cystine / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018698:Glutamic Acid / Q000097:blood* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D019169:Jurkat Cells; D016014:Linear Models; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D018950:Lipopolysaccharide Receptors; C118895:SLC7A11 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018698:Glutamic Acid; D003553:Cystine; D005978:Glutathione; D019803:Glutathione Disulfide