Hepatic expression of STAT1, SOCS3 & PIAS1 in HCV Patients and their Role in Response to therapy (original) (raw)
Related papers
Canadian Journal of Gastroenterology, 2013
BACKGROUND: The underlying mechanisms of hepatitis C virus (HCV) resistance to treatment are unknown. Signal transducers and activators of transcription (STAT) proteins play a critical role in antiviral defense.OBJECTIVE: To explore some of the mechanisms of HCV resistance to interferon, the expression of STAT1 and its negative regulators, protein inhibitor of activated STAT (PIAS1) and suppressor of cytokine signalling (SOCS3), in liver tissues of both inteferon responders and nonresponders in chronic HCV patients.METHODS: Sixty patients were divided into the following groups: group 1a comprised 38 treatment-responder chronic HCV patients; group 1b consisted of 22 treatment-nonresponder chronic HCV patients; and group 2 consisted of six control subjects. Liver biopsies were examined for histological scoring; STAT1, SOCS3 and PIAS1 expression was analyzed using Western blotting methods.RESULTS: STAT1 expression in the liver tissue of patients in group 1 was significantly increased c...
Gut, 2005
Background: Signal transducers and activators of transcription (STATs) play a critical role in antiviral defence. STAT3 is also important in cell protection against inflammatory damage. STAT proteins are activated by interferons and by hepatoprotective cytokines of the interleukin 6 superfamily, including cardiotrophin 1. Methods: We analysed the status of STATs in hepatitis C virus (HCV) infected livers and the relationship between expression and activation of STATs and HCV replication in Huh7 cells transfected with HCV genomic replicon. Results: STAT3a expression was reduced in HCV infected livers showing an inverse correlation with serum alanine aminotransferase. In patients with HCV infection, nuclear staining for phosphorylated STAT3 was faint in parenchymal cells (although conspicuous in infiltrating leucocytes), in contrast with strong nuclear staining in hepatocytes from control livers. Expression and activation of STAT1 (a factor activated by both interferon (IFN)-a and IFN-c) were increased in HCV infected livers, particularly in those with high inflammatory activity. Conversely, phosphorylated STAT2 (a factor selectively activated by IFN-a) was undetectable in livers with HCV infection, a finding that was associated with marked downregulation of the two functional subunits of the IFN-a receptor. HCV replication in Huh7 cells caused STAT3a downregulation and blocked STAT3 phosphorylation by either IFN-a or cardiotrophin 1. HCV replication in Huh7 cells also inhibited STAT1 and STAT2 activation by IFN-a while there was no impairment of STAT1 phosphorylation by the proinflammatory cytokine IFN-c. Conclusions: STAT3 is downregulated in HCV infected livers and in Huh7 cells bearing the full length HCV replicon. HCV replication is associated with impaired Jak-STAT signalling by antiviral and cytoprotective cytokines. These effects may favour viral replication while facilitating the progression of liver disease.
Khyber Medical University Journal, 2013
OBJECTIVE: to investigate the role of STAT1 in treatment failure in interferon resistant hepatitis C virus (HCV) infected patients. METHODOLOGY: Liver biopsies and blood from patients infected with HCV, resistant to interferon therapy were collected under sterile conditions in the laboratory of Army Medical College, Rawalpindi. Study included HCV infected patients who were positive for serum HCV RNA, and were non-responders to two courses of interferon therapy, IFN-α injection and ribavirin oral for 24 weeks periods. Study also included 10 controls i.e. 5 normal healthy subjects with normal LFTs who were negative for anti-HCV antibodies and 5 responder patients who responded to first course of interferon treatment and had normal LFTs. The liver biopsy specimens were subjected to PCR based detection of STAT1 and liver histopathology status evaluation. GeneJET™ RNA Purification Kit# K0731, Fermentas was used for total RNA isolation from liver biopsy specimen. The study was approved by institute's ethical committee. RESULTS: STAT1 mRNA was detected in 96.2% (n=25/26) of the HCV patients resistant to interferon therapy and in 100% of the normal as well as responders. Patient's distribution for histological activity index along with STAT1 mRNA expression was 68% in the score of 4-7 and 28% in the score of 8-12. CONCLUSION: STAT1 mRNA is being expressed by all the HCV infected patients resistant as well as responders to interferon therapy. STAT1 expression is not a major factor responsible for interferon resistance in HCV patients.
Journal of Medical Virology, 2019
Hepatitis C virus (HCV) is the leading cause of chronic liver complications globally and suppressor of cytokine signaling-1 (SOCS-1) is a gene triggered by cytokines that activates transcription of the JAK/STAT signal transduction pathway and negatively regulates Janus kinase-signal transducer. Several studies have shown that the expression of SOCS1 and SOCS3 genes negatively regulate the response of HCV infection to interferon therapy and interferon-free regimens. It has been reported that liver function enzymes elevate in CHC patients but the association of SOCS1 gene expression with LFTs haven't been studied. This study recruited 114 CHC patients and 112 normal healthy participants and analyzed the correlation of SOCS1 gene expression and liver function enzymes (LFEs). Herein, we observed that the expression of SOCS1 gene had a positive correlation with LFEs.
Biochemical Journal, 2004
IFN-γ (interferon-γ ) modulates IFN-α therapy in chronic hepatitis C infection; however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3-6 days) but not short-term (up to 1 day) IFN-γ treatment of human hepatoma Hep3B cells attenuates IFN-α activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3, but enhances IFN-γ and interleukin 6 activation of STATs. Prolonged exposure to IFN-γ also significantly induces STAT1 protein expression without affecting STAT2, STAT3 and ERK (extracellular-signal-regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression in regulation of IFN-α signalling, Hep3B cells were stably transfected with wild-type STAT1. Overexpression of STAT1 via stable transfection enhances IFN-γ activation of STAT1, but surprisingly attenuates IFN-α activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-α activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-α-activated STAT2 translocation from IFN-α receptor 2 to IFN-α receptor 1, a critical step in IFN-α signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-γ , are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-γ treatment inhibits IFN-α-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-α treatment failure in hepatitis C patients.
STAT-1 in Interferon Resistant HCV Pak Armed Forces Med
2015
Objective: To evaluate the expression of STAT-1 (Signal Transducers and Activators of Transcription-1) in HCV patients non responder to interferon treatment. Patients and Methods: The study after approved by institute's ethics committee was conducted on 15 HCV infected patients who were non responder to interferon therapy and 5 controls responder to interferon therapy. Their age, sex, body mass index (BMI) and marital status was noted. PCR based detection of STAT-1 mRNA was carried out in blood of HCV infected patients resistant to interferon therapy as well as controls. Data was presented in the form of frequencies and percentages and p values were calculated using Fisher exact test and student t-test. Results: Results showed that more males were resistant to interferon therapy as compared to females. The mean age was less in responders as compared to non responders. Forty percent of the HCV infected patients non responder to interferon therapy were positive for STAT-1 expressi...
Virology, 2006
Hepatitis C virus (HCV) infection is a major contributor to the development of end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC). We have previously shown that HCV core protein promotes immortalization of primary human hepatocytes. To identify molecular changes involved in core protein-mediated immortalization, we have investigated differential gene expression by microarray analyses in primary human hepatocytes and HCV core gene introduced hepatocytes after senescence (early passage), immortalization (middle passage), and anchor-independent growth (late passage). Out of 33,000 human genes screened, 1918 transcripts were differentially expressed (>2-fold) in immortalized human hepatocytes (IHH) as compared to negative controls. Our analyses provided a molecular portrait of changes in gene expression associated with three distinct stages of hepatocytes after introduction of HCV core gene. Many of the overall changes were involved with important cellular pathways, including cell growth regulation, immune regulation, oxidative stress, and apoptosis. We focused on the Stat3 signaling pathway by further verifying selected genes at the protein level relevant to hepatocyte growth regulation. Our data suggested that the introduction of HCV core protein results in an increase in expression of IL-6, gp130, leptin receptor, and Stat3. Upregulation of these genes in turn may regulate c-myc and cyclin D1, downstream of the Stat3 signaling pathway. Identification of these modulated genes with potential roles may help in the selection of targets for therapies against HCV-mediated liver disease progression.
STAT3 induces anti-hepatitis C viral activity in liver cells
Biochemical and Biophysical Research Communications, 2004
Hepatitis C virus (HCV) infection is a leading cause a of chronic liver disease worldwide. The main therapeutic regimen is the combination of interferon a (IFN) and the nucleoside analog, Ribavirin. IFN initiates an intracellular antiviral state by the JAK-STAT signaling pathway, including a presumed role for STAT1 and STAT2. We have previously shown that the STAT3 activation occurs during IFN treatment of human hepatoma cells, suggesting that the STAT3-mediated pathway is relevant to IFN-induced antiviral activity. In this study, we investigate the role of activated STAT3 in the induction of anti-HCV activity in human hepatoma cells. We demonstrate that the STAT3 activation is involved in efficient IFN-induced anti-HCV activity. Using an inducible, cytokine-independent, STAT3 activation system, in which the entire coding region of STAT3 is fused with the ligand-binding domain of the estrogen receptor, we demonstrate that: activated STAT3 is tightly regulated in a stably transfected cell line by an estrogen analog, 4-HT; activated STAT3 initiates efficient anti-HCV activity in a HCV subgenomic replicon cell line; and activation of STAT3 is associated with the induction of a potential antiviral gene, 1-8U. In addition, we show that the cytokine IL-6, a potent STAT3 activator, inhibits HCV subgenomic RNA replication through STAT3 activation and ERK pathway. These results strongly suggest that STAT3 activation is capable of initiating intracellular antiviral pathways.