Enhanced Expression of Interferon-Regulated Genes in the Liver of Patients with Chronic Hepatitis C Virus Infection: Detection by Suppression-Subtractive Hybridization

Patzwahl, René; Meier, Volker; Ramadori, Giuliano; Mihm, Sabine

doi:10.1128/jvi.75.3.1332-1338.2001

Cited by 97 publications

(93 citation statements)

References 52 publications

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“…[22][23][24][25][26][27] Taken together, these studies suggest that the HCV chronically infected liver is capable of mounting an antiviral response. It is therefore intriguing to postulate why HCV is not cleared from these individuals given a number of classic antiviral genes such as OAS and MxA and genes with anti-HCV activity such as ISG6-16 5 and ISG-56 6 are increased in expression.…”

Section: Discussionmentioning

confidence: 72%

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

et al. 2005

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Interferon (IFN) ␣ inhibits hepatitis C virus (HCV) replication both clinically and in vitro;however, the complete spectrum of interferon-stimulated genes (ISGs) expressed in the HCV-infected liver or the genes responsible for control of HCV replication have not been defined. To better define ISG expression in the chronically infected HCV liver, DNA microarray analysis was performed on 9 individuals with chronic hepatitis C (CHC). A total of 232 messenger RNAs were differentially regulated in CHC compared with nondiseased liver controls. A significant proportion of these were potential ISGs that were transcriptionally elevated, suggesting an ongoing response to endogenous IFN and/or double-stranded RNA. H epatitis C virus (HCV) is the leading cause of chronic hepatitis and liver disease-related morbidity worldwide. A significant proportion of infected individuals escape the host antiviral response and develop a chronic infection, which can result in progressive liver disease such as cirrhosis and hepatocellular carcinoma. 1 The current and only therapy for chronic hepatitis C (CHC) infection is interferon (IFN) ␣/ribavirin combination therapy that results in response rates to sustained viral clearance in at best 50% of patients. Clearly a significant number of individuals cannot be cured of HCV infection, many of whom will progress to serious liver disease.Viral infection activates the host innate antiviral response, which results in the induction of cellular protective genes, including type I IFNs (IFN-␣ and IFN-␤), proinflammatory cytokines, and a subset of interferonstimulated genes (ISGs) that directly limit viral replication. 2,3 Microarray studies in vitro have revealed that hundreds if not thousands of ISGs may be expressed in response to stimulation with IFN, some of which are known to have direct antiviral and immunomodulatory action. 4 Of the best-characterized antiviral ISGs, MxA, double-stranded RNA (dsRNA)-activated protein kinase R, and 2Ј-5Ј-oligoadenylate synthesase (OAS) are most renowned; however, the complete spectrum of ISGs has not been identified, thus ISGs with potential antiviral action remain unknown. The ISGs that limit HCV replication at the molecular level are ill-defined, although recent work has shown that ISG6-16 can enhance the anti-HCV activity of IFN-␣, 5 and ISG-56 has direct anti-HCV activity through its ability to suppress HCV IRES

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Section: Discussionmentioning

confidence: 72%

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

et al. 2005

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“…For instance, the analysis of a subtracted library (transcriptome of an HCV-infected liver tissue minus that of noninfected tissues with similiar histopathological changes) revealed an enhanced expression of some IFN-regulated genes but not that of type I IFN genes themselves. 15 Moreover, when HCV-associated liver cirrhosis was compared to nondiseased liver tissue, a limited gene expression analysis using a cDNA microarray of 874 genes revealed the induction of the type I IFN-inducible peptide 6-16 in the absence of IFN-a 2 . 37 A more comprehensive oligonucleotide microarray analysis of more than 9000 genes documented a higher expression of four IFNinducible genes in HCV-associated hepatocellular carcinoma specimens than in noninfected nontumorous liver, but not that of type I IFN genes.…”

Section: Discussionmentioning

confidence: 99%

“…The liver of hepatitis C patients expresses interferon-inducible protein 10 (IP-10), a chemokine that attracts monocytes and activated T-helper cells. 15,[46][47][48] The main producers of type I IFNs, however, are the so-called natural IFN producing cells (IPCs) or plasmacytoid dendritic cells (pDCs). 9 Despite expression of very high levels of the IP-10 receptor CXCR3, natural IFN producing cells do not respond efficiently to CXCR3 ligands.…”

Section: Discussionmentioning

confidence: 99%

“…29 It has been shown previously that liver biopsy samples of hepatitis C patients contain elevated MxA mRNA levels along with those of other type I IFN-regulated genes. 15,30,31 To find out whether the observed expression of type I IFN-regulated genes in HCV-infected livers might be induced by intrahepatically produced IFNs, we took liver specimens from patients with chronic hepatitis C, liver disorders unrelated to viral infections, and a suspected but later excluded liver disease and analyzed the samples for the expression of type I IFN genes and that of type I IFN-regulated genes by using quantitative RT-PCR techniques (for details, see the Materials and methods section). In line with previous findings, we found that MxA is highly expressed in the liver of hepatitis C patients.…”

Section: Expression Of Mxa Ifn-a Ifn-b and Ifn-k In The Liver Of Hmentioning

confidence: 99%

“…11,14 A previous approach comparing gene expression in HCV-infected liver tissues with that in noninfected livers by using the technique of suppression subtractive hybridization revealed an enhanced (ie greater than five-fold) expression of some IFN-regulated genes in the HCV-infected livers. 15 Among these are the type I IFN-regulated genes MxA, interferon inducible protein 44 (IFI-44), and interferon inducible protein 56 (IFI-56K). On the one hand, these data indicate that especially those genes that are upregulated in chronic hepatitis C might not be those that are capable to inhibit HCV replication sufficiently.…”

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Interferon type I gene expression in chronic hepatitis C

Mihm

Frese

Meier

et al. 2004

Laboratory Investigation

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Hepatitis C virus (HCV) frequently causes chronic liver disease. The cause of viral persistence might be an inappropriate type I interferon (IFN) induction. To analyze the host's IFN response in chronic hepatitis C, we measured the transcription level of type I IFN genes as well as type I IFN-regulated genes in liver tissue and corresponding blood samples from patients with chronic hepatitis C, nonviral liver diseases, and a suspected but later excluded liver disease. Competitive and real-time RT-PCR assays were used to quantify the messenger RNA (mRNA) levels of all known IFN-a, IFN-b, and IFN-k genes and those of some IFN-regulated genes. We failed to detect any hepatic type I IFN mRNA induction, although liver tissue of chronic hepatitis C patients contained high numbers of some type I IFN-inducible effector mRNA molecules. Analysis of peripheral blood samples, however, showed a clear type I IFN induction. Parallel experiments employing HCV replicon cell lines revealed that replication of HCV RNA is not sufficient to induce any type I IFN nor to induce directly type I IFN-regulated genes such as MxA. In conclusion, our data provide evidence for the absence of an induction of type I IFN genes by HCV in the human liver and argue for a further development of type I IFN-based therapies.

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Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

Wald¹,

et al. 2004

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Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV-and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-bloodvessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.

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Enhanced Expression of Interferon-Regulated Genes in the Liver of Patients with Chronic Hepatitis C Virus Infection: Detection by Suppression-Subtractive Hybridization

Abstract: Hepatitis C virus (HCV) infection causes

Cited by 97 publications

References 52 publications

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

Interferon type I gene expression in chronic hepatitis C

Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

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