title: Enhanced expression of suppressor of cytokine signalling-1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy.
abstract: Interferon-alpha (IFN-alpha) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK-STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN-alpha is demonstrated here. The transcriptional levels of SOCS-1 and -3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription-polymerase chain reaction. We established stable transfectants of SOCS-1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS-1 on the phosphorylation of IFN-alpha-induced STAT-1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS-1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS-1, but not SOCS-3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN-alpha-induced STAT-1 phosphorylation and the expression of antiviral genes were inhibited in SOCS-1-transfected cells. Patients showing high SOCS-1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS-1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS-1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS-1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Imanaka
authors.forename: S
authors.initials: S
authors.lastname: Tamura
authors.forename: K
authors.initials: K
authors.lastname: Fukui
authors.forename: N
authors.initials: N
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Kiso
authors.forename: Y
authors.initials: Y
authors.lastname: Imai
authors.forename: T
authors.initials: T
authors.lastname: Naka
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
authors.forename: S
authors.initials: S
authors.lastname: Kawata
authors.forename: Y
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
chemical_list: D005819:Genetic Markers; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins