| Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: A vicious circle of clinical significance? | |
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MedLine Citation:
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PMID: 21538438 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Insulin resistance (IR) is common in chronic hepatitis C (CHC) and associates with reduced virological response to Pegylated-Interferon (PEG-IFN)/Ribavirin therapy, but the underlining mechanisms are still unclear. We have previously shown that, in CHC patients, insulin plasma levels are inversely related to antiviral effect induced by PEG-IFN. Therefore, we have here investigated "in vitro" the effect of insulin on IFN-alpha intracellular signaling as well as that of IFN-alpha on insulin signaling. HepG2 cells, pre-incubated with or without insulin, were stimulated with IFN-alpha2b and mRNA and protein expression of IFN-stimulated genes (ISGs) were measured at different time points. The role of intracellular SOCS3 was evaluated by the siRNA strategy. To assess the effect of IFN-alpha on insulin signaling, HepG2 were pre-incubated with or without IFN before addition of insulin and cells were then analyzed for IRS-1 and for Akt/PKB Ser473 phosphorylation. Insulin (100 and 1000nM) significantly reduced in a dose-dependent fashion IFN-induced gene expression of PKR (p=0.017 and p=0.0017, respectively), MxA (p=0.0103 and p=0.00186) and OAS-1 (p=0.002 and p=0.006). Insulin also reduced IFN-alpha induced PKR protein expression. Although insulin was confirmed to increase SOCS3 expression, siRNASOCS3 did not restore ISGs expression after insulin treatment. IFN-alpha was found to reduce, in dose dependent fashion, IRS-1 gene expression as well as Akt/PKB Ser473 phosphorylation induced by insulin. CONCLUSIONS: These results provide evidence of reciprocal interference between insulin and IFN-alpha signaling in liver cells. These findings may contribute to understand the role of insulin in CHC: IR might be favored by endogenous cytokines including IFN-alpha, and the resulting hyperinsulinemia then reduces the antiviral response to exogenous IFN in a vicious circle of clinical significance. (HEPATOLOGY 2011.). |
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Authors:
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L Franceschini; S Realdon; M Marcolongo; S Mirandola; G Bortoletto; A Alberti |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-29 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-5-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Association for the Study of Liver Diseases. |
Affiliation:
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Venetian Institute of Molecular Medicine-VIMM, Padova, Italy. |
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