title: Altered interferon-alpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection.
abstract: OBJECTIVE
  Natural killer (NK) cells play an important role in the immune response against virus infection. Interferon (IFN)-alpha, an essential component in therapy against hepatitis C virus (HCV) infection, regulates NK cell function. However, it remains obscure how chronic HCV infection (CHC) modifies intracellular IFN-alpha signaling in NK cells. We investigated IFN-alpha signaling in NK cells in patients with CHC.
  
  
  METHODS
  Peripheral blood mononuclear cells were obtained from patients with CHC and healthy subjects (HS) as controls.
  
  
  RESULTS
  The expression level of signal transducer and activator of transcription (STAT) 1, a key molecule of IFN-alpha signaling, was clearly higher in NK cells from the CHC patients than in those from HS. The phosphorylation level of STAT1 with IFN-alpha stimulation was significantly greater in NK cells from the CHC patients than in those from the HS, while that of STAT4 was significantly less. These phosphorylation levels of STAT1 and STAT4 positively and negatively correlated with the STAT1 level in NK cells, respectively. The IFN-alpha induced messenger RNA level of the suppressor of cytokine signaling 1, which is a downstream gene of phosphorylated-STAT1, was clearly greater in NK cells from the CHC patients than in those from the HS, while that of IFN-gamma, which is a downstream gene of phosphorylated-STAT4, was clearly lower.
  
  
  CONCLUSIONS
  These results indicate altered IFN-alpha signaling in NK cells in CHC patients, suggesting that this alteration is associated with the persistence of HCV infection and resistance to IFN-alpha therapy.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nishio
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kohga
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma