Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: A vicious circle of clinical significance?
✍ Scribed by Lisa Franceschini; Stefano Realdon; Moira Marcolongo; Silvia Mirandola; Gladis Bortoletto; Alfredo Alberti
- Book ID
- 102851060
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 738 KB
- Volume
- 54
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
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 underlying 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 investigated the in vitro effect of insulin on interferon alpha (IFN-α) intracellular signaling as well as that of IFN-α on insulin signaling. HepG2 cells, preincubated with or without insulin, were stimulated with IFN-α2b and messenger RNA (mRNA) and protein expression of IFN-stimulated genes (ISGs) were measured at different timepoints. The role of intracellular suppressors of cytokine signaling 3 (SOCS3) was evaluated with the small interfering RNA (siRNA) strategy. To assess the effect of IFN-α on insulin signaling, HepG2 were preincubated 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 1000 nM) 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 2'-5' oligoadenylatesynthetase 1 (OAS-1) (P=0.002 and P=0.006). Insulin also reduced IFN-α-induced PKR protein expression. Although insulin was confirmed to increase SOCS3 expression, siRNA SOCS3 did not restore ISG expression after insulin treatment. IFN-α was found to reduce, in a dose-dependent fashion, IRS-1 gene expression as well as Akt/PKB Ser473 phosphorylation induced by insulin.
Conclusion:
These results provide evidence of reciprocal interference between insulin and ifn-α 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-α, and the resulting hyperinsulinemia then reduces the antiviral response to exogenous ifn in a vicious circle of clinical significance.