The Role of Hepatic Expression of STAT1, SOCS3 and PIAS1 in the Response of Chronic Hepatitis C Patients to Therapy

Saadany, Sherif El; Ziada, Dina Hazem; Bassat, Hanan El; Farrag, Wael; El-Serogy, Hesham; Eid, Manal A.; Abdallah, Manal; Ghazy, Medhat; Salem, Hoda A.

doi:10.1155/2013/562765

Cited by 18 publications

(11 citation statements)

References 20 publications

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“…As Th17-derived IL-6 and IL-21 could block the differentiation of Tregs [ 47 ], we propose that increased expressions of IL-21 mRNA by IL-23 agonist could might have caused a corresponding reduction in the FoxP3 mRNA expressions. Importantly, our data on the mRNA expressions of IL-17A, IL-22, STAT1, SOCS3, MxA, and FoxP3 in the PBMCs are consistent with the changes of these cytokines in livers reported in other studies [ 48 , 49 , 50 , 51 , 52 ]. Our data also suggest that the imbalance of T-cell subsets distribution might have important influences on disease progression and clinical outcome.…”

Section: Discussionsupporting

confidence: 92%

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Meng

Zhao

Niu

et al. 2016

IJMS

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Interleukin-23 (IL-23) and its downstream factor IL-17 are the key cytokines involved in immune and inflammatory response in chronic liver diseases. This study aimed to investigate the role and molecular mechanisms of the IL-23/Th17 axis in chronic hepatitis C virus (HCV) infection, and the efficacy of IL-23/Th17 modulation in response to anti-HCV therapy. Sixty-six HCV-infected patients and 20 healthy controls were enrolled. The patients received PegIFNa-2a and ribavirin therapy for at least 48 weeks. The plasma level of IL-23 and the number of IL-17A-, IFN-γ-, and IL-21-producing peripheral blood mononuclear cells (PBMCs) at baseline and 12, 24, and 48 weeks following treatment were determined. The mRNA level of Th17 immune-associated molecules in PBMCs was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) following treatment with IL-23 agonist or antagonist. Our data showed that, compared to healthy controls, HCV-infected patients had an increased plasma level of IL-23 and increased frequencies of IL-17A- and IFN-γ-producing PBMCs, whereas the HCV patients exhibited a reduced number of IL-21-producing PBMCs. However, the baseline frequencies of IL-21-producing PBMCs were markedly higher in HCV patients who achieved rapid virological response (RVR) than those without RVR. Additionally, the mRNA expressions of IL-21, IFN-γ, myxovirus resistance protein A (MxA), and suppressor of cytokine signaling 3 (SOCS3) were significantly upregulated in PBMCs, while FoxP3 expression was suppressed by IL-23 agonist. Thus, the IL-23/Th17 axis plays an important role in development of chronic HCV infection and antiviral response. IL-23 may enhance the antiviral activity of interferon-based therapy by modulating the expression of Th17 cells-associated molecules in HCV-infected patients.

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Section: Discussionsupporting

confidence: 92%

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Meng

Zhao

Niu

et al. 2016

IJMS

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“…In addition, miRNAs are increasingly considered to be regulators of SOCS expression ( 185 ). For example, studies have shown that inhibiting the expression of miRNA-122 to enhance promoter methylation to inhibit the expression of SOCS3 is a promising option for the treatment of HCV ( 186 – 188 ). Until recently, IL-7 therapy has also been shown to improve the immune response to persistent infections caused by HIV, HBV and HCV by targeting SOCS3 ( 189 ).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

SOCS Proteins Participate in the Regulation of Innate Immune Response Caused by Viruses

et al. 2020

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The host immune system has multiple innate immune receptors that can identify, distinguish and react to viral infections. In innate immune response, the host recognizes pathogen-associated molecular patterns (PAMP) in nucleic acids or viral proteins through pathogen recognition receptors (PRRs), especially toll-like receptors (TLRs) and induces immune cells or infected cells to produce type I Interferons (IFN-I) and pro-inflammatory cytokines, thus when the virus invades the host, innate immunity is the earliest immune mechanism. Besides, cytokine-mediated cell communication is necessary for the proper regulation of immune responses. Therefore, the appropriate activation of innate immunity is necessary for the normal life activities of cells. The suppressor of the cytokine signaling proteins (SOCS) family is one of the main regulators of the innate immune response induced by microbial pathogens. They mainly participate in the negative feedback regulation of cytokine signal transduction through Janus kinase signal transducer and transcriptional activator (JAK/STAT) and other signal pathways. Taken together, this paper reviews the SOCS proteins structures and the function of each domain, as well as the latest knowledge of the role of SOCS proteins in innate immune caused by viral infections and the mechanisms by which SOCS proteins assist viruses to escape host innate immunity. Finally, we discuss potential values of these proteins in future targeted therapies.

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“…Furthermore, HCV core protein expression was reported to induce SOCS3 overexpression and IRS degradation, leading to IFN-␣ signaling impairment (31,70). Interestingly, SOCS3 expression was shown to be an independent predictor of IFN-␣ treatment response, especially in genotype 1-infected patients (71,72). It was also demonstrated, in a non-infected mouse model, that overexpression of SOCS induces IRS1 and IRS2 degradation, subsequently inducing insulin resistance (44).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice

Lerat

Imache

Polyte

et al. 2017

Journal of Biological Chemistry

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Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.

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The Role of Hepatic Expression of STAT1, SOCS3 and PIAS1 in the Response of Chronic Hepatitis C Patients to Therapy

Cited by 18 publications

References 20 publications

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

SOCS Proteins Participate in the Regulation of Innate Immune Response Caused by Viruses

Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice

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