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Steatohepatitis/Metabolic Liver Disease
Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: A vicious circle of clinical significance?†
Article first published online: 23 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 2, pages 484–494, August 2011
How to Cite
Franceschini, L., Realdon, S., Marcolongo, M., Mirandola, S., Bortoletto, G. and Alberti, A. (2011), Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: A vicious circle of clinical significance?. Hepatology, 54: 484–494. doi: 10.1002/hep.24394
Potential conflict of interest: Nothing to report.
- Issue published online: 25 JUL 2011
- Article first published online: 23 JUN 2011
- Accepted manuscript online: 29 APR 2011 11:11AM EST
- Manuscript Accepted: 17 APR 2011
- Manuscript Received: 12 MAR 2011
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. (HEPATOLOGY 2011;)
Chronic infection with the hepatitis C virus (HCV) is a major cause of liver disease in many parts of the world,1 leading to endstage complications that include cirrhosis, liver decompensation, and hepatocellular carcinoma.2, 3 More than 20 years ago, interferon alpha (IFN-α) was introduced in the treatment of HCV chronic infection and, also thanks to the subsequent development of pegylated formulations with improved pharmacokinetics,4, 5 it is still considered the ideal backbone therapy for current and future therapeutical interventions.6 The mechanisms of action of IFN-α in controlling HCV are certainly complex and multifactorial but there is large body of evidence supporting an important role of direct antiviral effects in the infected hepatocytes.7 Induction of antiviral effector genes by IFN signal transduction has been shown to inhibit HCV replication in vitro,8, 9 and is considered of paramount importance in determining the earliest kinetics of response in patients treated with IFN-based regimens.10-12 Several factors may affect IFN signaling in infected hepatocytes, thus influencing the quality and potency of the antiviral response.13 Many data indicate that HCV patients with a concomitant state of insulin resistance (IR) display a reduced antiviral response when treated with pegylated (PEG)-IFN/ribavirin combination therapy and this is largely independent of other variables known to affect the response such as HCV genotype and load or race or stage of liver disease.14-19 In this regard, we have recently shown that a significant impairment in the antiviral response to PEG-IFN in the presence of IR is evident as early as 24 hours after the first injection of the drug, as shown by a slower decay in serum HCV-RNA levels.20 Our data provided convincing evidence for a highly significant, linear inverse relationship between HCV-RNA decay and serum insulin levels, measured at the time of IFN administration, suggesting some kind of direct interference of insulin on IFN signaling. The molecular link between IR and reduced response to IFN-α has been suggested to lie in an activation of the suppressors of cytokine signaling (SOCS)-3 in the liver by HCV, in the attempt by the virus to contrast the host innate immune response.21-26 These concepts have produced a number of studies aimed to assess whether drugs able to restore insulin sensitivity may improve responsiveness to IFN-α in patients with HCV and IR. These studies, however, have generated inconsistent or conflicting results, and it is still unclear how to optimize antiviral therapy in HCV patients with IR.27-29 Although IR and reduced response to IFN may represent two parallel, but distinct effects of SOCS3 overexpression in infected hepatocytes, the impressive inverse correlation we observed between baseline insulin levels and the very early antiviral response to IFN therapy may indicate direct interference between insulin and IFN signaling in hepatocytes, independent of a role of HCV.
To explore this possibility, we used human hepatocyte cell lines to investigate the effect of insulin on gene and protein expression of IFN-stimulated genes such as myxovirus resistance protein A (MxA), 2′-5′ oligoadenylatesynthetase 1(OAS-1), and double-stranded RNA (dsRNA)-dependent protein kinase (PKR), which are thought to be the main mediators of the intracellular direct antiviral effects of IFN-α. Using the same cell line, we also investigated the effect of IFN-α on insulin signaling. The results obtained are in favor of reciprocal interference between IFN-α and insulin signaling in liver cells. Our findings may explain the increased frequency of IR seen in patients with chronic HCV infection and the reduced response to IFN-based therapy in these patients as the consequence of a vicious circle in which endogenous IFN and cytokines induce IR and the resulting hyperinsulinemia reduces the therapeutic response to exogenous IFN-α.
Materials and Methods
The reciprocal effects between insulin and IFN-α signaling were studied in cultured HepG2 cells. In the first set of experiments, cells were pretreated with different concentrations of insulin, stimulated with IFN-α2b, and then analyzed for three classic IFN-stimulated genes (PKR, MxA, and OAS-1), involved in the antiviral response, and for PKR protein expression. To assess the effect of IFN-α on insulin signaling, cells were pretreated with different concentrations of IFN-α2b, stimulated with insulin, and then analyzed for Akt/PKB Ser473 phosphorylation as well as for IRS-1 gene expression. The possible role of SOCS3 as mediators of insulin/IFN signaling interplay was investigated by specific silencing using the small interfering RNA (siRNA) technique.
HepG2 were cultured in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS), low glucose (1 g/L), 100 U/mL penicillin, and 100 μg/mL streptomycin (Invitrogen, Carlsbad, CA) at 37°C in a humidified 5% CO2 incubator. Cells were serum-starved 8 hours before experimental treatments. Insulin was obtained from Lilly (Suisse SA, Vernier, Switzerland) and recombinant IFN-α2b (INTRON A) from Schering Plough (Kenilworth, NJ). The HepG2 cells used in our experiments were shown to express the TT genotype at the rs12979860 position of the IL28B gene by real-time polymerase chain reaction (PCR).
Analysis of the Effect of Insulin on IFN-α Signaling.
Cells were exposed for 12 hours to either control media or 100 nM or 1,000 nM insulin supplemented with 1% FBS (Phase A). Cells were then incubated for additional 12 hours with IFN-α2b (100 IU/mL) or control medium (Phase B). During Phase B, cells were harvested at different timepoints (2, 4, 8, and 12 hours) to be analyzed for PKR, MxA, and OAS-1 gene expression and PKR protein expression. All experiments were performed at each timepoint in quadruplicate and the effect of insulin was investigated by comparison of IFN-α2b stimulated cells in the presence or absence of preincubation with insulin.
Analysis of the Effect of IFN-α on Insulin Signaling.
Cells were exposed for 12 hours to either control media or 1, 10, 100 IU/mL recombinant IFN-α2b supplemented with 1% FBS (Phase A1). Cells were then incubated for additional times with insulin (100 nM) or control medium (Phase B1). During Phase B1, cells were harvested at 15 minutes to be analyzed for Akt/PKB phosphorylation, and at 2, 4, 8, and 12 hours for IRS-1 gene expression. All experiments at each timepoint were performed in quadruplicate and the effect of IFN-α2b was investigated by comparison of insulin-stimulated cells in the presence or absence of preincubation with IFN-α2b.
Cell were lysed with detergent buffer (1% Triton X-100, 2% sodium dodecyl sulfate [SDS], 50 mM Tris, pH 7.5, 150 mM NaCl, 10 mM MgCl2, 0,5 mM DTT, 1 mM EDTA, 10% glycerol, protease inhibitor cocktail [Complete Mini, Roche Diagnostics] and phosphatase inhibitor cocktail [PhosSTOP, Roche Diagnostics]). Proteins (30 μg) were subjected to electrophoresis on polyacrylamide gel (Invitrogen, Life Technologies), transferred to nitrocellulose membrane (Bio-Rad, Hercules, CA). Blots were probed with antibodies to PKR, phosphorylated Akt/PKB, total Akt/PKB or β-actin (Cell Signaling Technology). Finally, proteins were detected with SuperSignalWestPico Chemiluminescent Substrate (Pierce, Rockford, IL) and exposed to film (Kodak). Protein levels were quantified using Gel-Pro Analyzer software.
Total RNA was isolated using Trizol Reagent (Invitrogen). Complementary DNA was synthesized with random hexanucleotides and SuperScript II RNase H(-) reverse-transcriptase kit (Invitrogen, Life Technologies).
Real-time quantitative PCR was performed using a LightCycler (Roche Diagnostic, Branchburg, NJ). ProbeFinder software on the Assay Design Center (http://www.roche-applied-science.com) was used to find the better association between primer pairs and probes. PKR, MxA, OAS-1, IRS-1, and SOCS3 amplification was performed using the following oligonucleotides: PKR_f 5′-TTTGGACAAAGCTTCCAACC-3′ and PKR_r 5′-CGGTATGTATTAAGTTCCTCCATGA-3′, probe #62; MxA_f 5′-TCCAGCCACCATTCCAAG-3′ and MxA_r 5′-CAACAAGTTAAATGGTATCACAG AGC-3′, probe #2; OAS-1_f 5′-CATCCGCCTAGTC AAGCACT-3′ and OAS-1_r 5′-CAGGAGCTCCAGG GCATAC-3′, probe #87; SOCS3_f 5′-AGACTTCGA TTCGGGACCA-3′ and SOCS3_r 5′-AACTTGCTGT GGGTGACCA-3′, probe #36, IRS-1_r 5′-TATGCCA GCATCAGTTTCCA-3′ and IRS-1_f 5′-TTGCTGAG GTCATTTAGGTCTTC-3′, probe #71. For glyceraldehyde-3-phosphate dehydrogenase (GAPDH), used as internal control, the following primers and probe were used: GAPDH_f 5′-AGCCACATCGCTCAGACAC-3′ and GAPDH_r 5′-GCCCAATACGACCAAATCC-3′, probe #60. The amount of every messenger RNA (mRNA) was determined using the standard curve method. To generate standard curve, amplicons of each gene were cloned into a standard vector, and 10-fold serially diluted samples of the plasmids (from 106 to 102 molecules/μL) were used. We normalized all data to GAPDH expression. Then values were expressed as the ratio between stimulated and untreated.
SOCS3 RNA Interference.
Cells were transfected with siRNA for SOCS3 (100 nM) (Dharmacon) using TransFast (Promega). The transfection success was evaluated by flow cytometry using fluorescent siRNA. Scramble siRNA were used as a negative control for siRNA. In order to study the silencing of SOCS3 gene expression, starved cells were transfected and stimulated with insulin and IFN-α2b alone or in combination using different concentration and incubation times of these two reagents.
Insulin plus siRNA for SOCS3 treatment was performed using cells transfected with siRNA for SOCS3 and finally incubated for 24 hours with insulin at a concentration of 100 nM.
Insulin plus scramble siRNA treatment was performed using cells transfected with scramble siRNA and finally incubated for 24 hours with insulin at a concentration of 100 nM.
Insulin plus siRNA for SOCS3 and IFN-α2b combination treatment was performed using cells transfected with siRNA for SOCS3, incubated with insulin at a concentration of 100 nM for 12 hours, and then stimulated with IFN-α2b at a concentration of 100 IU/mL for 8 hours.
Insulin plus scramble siRNA and IFN-α2b combination treatment was performed using cells transfected with scramble siRNA, incubated with insulin at a concentration of 100 nM for 12 hours, and then stimulated with IFN-α2b at a concentration of 100 IU/mL for 8 hours.
For each experiment, selected timepoints (2, 4, 8, and 12 hours) were analyzed and performed in quadruplicate.
Continuous variables are provided as means ± standard deviation (SD). Statistical analysis was done with Statistica software (v. 6.0) (StatSoft, Tulsa, OK). Comparison between groups was made using Student's t test. Differences were considered as significant when P < 0.05 (*), P < 0.01 (**), or P < 0.001 (***).
Insulin Reduces IFN-α-Mediated PKR Protein Expression.
The effect of insulin on IFN-α intracellular signaling was first investigated with the quantification of PKR protein expression using a western blot analysis (Fig. 1A,B). Control mock treatment with insulin alone (100 nM) had no effect on PKR protein expression. As expected, stimulation with IFN-α2b alone (100 IU/mL) increased PKR protein levels, the highest levels being observed after 12 hours. A significant reduction in PKR protein levels was observed when HepG2 were preincubated with insulin (100 nM) before stimulation by IFN-α2b (100 IU/mL).
Insulin Affects IFN-α-Mediated Gene Expression.
To evaluate if insulin inhibited IFN-α signaling, PKR, MxA, and OAS-1 gene expressions were examined in HepG2 pretreated with insulin for 12 hours (Figs. 2, 3, 4). Insulin itself (100 nM) had no effect on the expression of PKR, MxA, and OAS-1 mRNA. On the contrary, and as expected, IFN-α2b (100 IU/mL) alone induced a rapid overexpression of these ISGs mRNA, the highest levels being observed after 8 hours of stimulation: PKR (t2 = 1.45 ± 0.54; t4 = 4.67 ± 1.99; t8 = 6.48 ± 0.76; t12 = 4.06 ± 1.77); MxA (t2 = 22.47 ± 14.28; t4 = 638.83 ± 429.44; t8 = 2102.79 ± 985.60; t12 = 1101.10 ± 81.36) and OAS-1 (t2 = 1.10 ± 0.20; t4 = 1.71 ± 1.31; t8 = 5.73 ± 0.72; t12 = 2.17 ± 1.64). When cells were preincubated with insulin followed by IFN-α2b, a significant decrease in PKR, MxA, and OAS-1 gene expression was observed when compared to cells not exposed to insulin before stimulation with IFN-α. Indeed, with 100 nM insulin pretreatment mean PKR mRNA levels were t4 = 2.15 (P = 0.046 versus cells not exposed to insulin), t8 = 3.96 (P = 0.009), t12 = 3.32 (P = NS), (Fig. 2); mean MxA mRNA levels were: t4 = 195.58 (P = NS), t8 = 644.69 (P = 0.022), t12 = 556.79 (P = 0.0003), (Fig. 3); mean OAS-1 mRNA levels: t4 = 0.80 (P = NS), t8 = 2.79 (P = 0.003), t12 = 2.04 (P = NS) (Fig. 4).
The inhibitory effect of insulin was dose-dependent, being higher at 1,000 nM compared to 100 nM (Figs. 2-4) and this was particularly evident when data were expressed as AUC (area under the curve), of total mRNA produced. Mean AUC values (from four experiments at each timepoint) were the following: PKR = 38.97 ± 8.60; 19.94 ± 8.03; 11.46 ± 0.01 with IFN-α2b alone, IFN-α2b + insulin100 nM; IFN-α2b + insulin1000 nM respectively (Fig. 2). MxA = 12,531.89 ± 4,667.98; 3,679.34 ± 1158.01; 949.04 ± 100.07 with IFN-α2b alone, IFN-α2b + insulin100 nM; IFN-α2b + insulin1000 nM, respectively (Fig. 3). OAS-1 = 24.63 ± 5.58; 7.1 ± 3.76; 1.37 ± 1.36 with IFN-α2b alone, IFN-α2b + insulin100 nM; IFN-α2b + insulin1000 nM, respectively (Fig. 4). These differences were all statistically significant (Figs. 2-4).
Insulin Inhibition of IFN-Dependent ISGs Expression Is Not Mediated by SOCS3.
Because insulin (100 nM) induced significant expression of SOCS3 in HepG2 cells (Fig. 5A) and SOCS3 are well known inhibitors of IFN signaling, we aimed to verify if insulin-induced inhibition of IFN-α2b signaling could be mediated by SOCS3. For this purpose, siRNA technology was used. HepG2 were transfected with SOCS3-siRNA and transfection efficiency, evaluated by flow-cytometry, was higher than 80% (data not shown). In preliminary time course experiments (data not shown), real-time PCR quantification showed that the highest silencing effect on SOCS3 mRNA levels occurred after 24 hours of both siRNA transfection and insulin (100 nM) stimulation: at this timepoint SOCS3-siRNA was able to completely inhibit insulin-mediated SOCS3 overexpression (Fig. 5A).
In order to study the effect of SOCS3 silencing on IFN-α signaling, HepG2 was incubated with both insulin and IFN-α2b and then transfected with SOCS3-siRNA. Silencing of SOCS3 had no effect on PKR, MxA, and OAS-1 mRNA levels when compared to control cells incubated with insulin and IFN-α2b (Fig. 5B) suggesting that SOCS3 overexpression has no pivotal role in the insulin-mediated inhibition of IFN signaling.
IFN-α Inhibits Insulin-Stimulated Akt/PKB Ser473 Phosphorylation in a Dose-Dependent Manner.
The status of Ser473 phosphorylation of Akt/PKB is considered a marker of insulin intracellular signaling activation. Western blot analysis was performed to evaluate the effects of IFN-α2b on insulin signaling. Control treatment with insulin alone (100 nM) increased Akt/PKB Ser473 phosphorylation (Fig. 6A,B), as expected. IFN-α2b treatment alone (100 IU/mL) did not induce Akt/PKB activation. Cells preincubated with increasing concentrations of IFN-α2b (1, 10, 100 IU/mL) and then stimulated with insulin (100 nM) showed a progressively reduction on insulin-stimulated Akt/PKB Ser473 phosphorylation (Fig. 6 A,B).
IFN-α Inhibits Insulin-Dependent IRS-1 Expression.
The inhibitory effect of IFN-α2b on insulin signaling was also evaluated on IRS-1 gene expression, which is known to be an insulin-dependent gene.
Cells were pretreated with IFN-α2b for 12 hours. Figure 7 demonstrates that 100 IU/mL IFN-α2b had no effect on the expression of IRS-1 mRNA (t2 = 1.74 + 0.23; t4 = 1.34 + 0.18; t8 = 1.35 + 0.12; t12 = 1.48 + 0.45). On the contrary and as expected, insulin alone (100 nM) induced IRS-1 overexpression, the highest level being observed after 8 hours of stimulation: IRS-1 (t2 = 1.8 + 0.18; t4 = 2.5 + 0.16; t8 = 2.67 + 0.1; t12 = 2.24 + 0.13). When cells were preincubated with IFN-α2b (100 IU/mL) followed by addition of insulin, a significant decrease of IRS-1 gene expression was observed when compared to cells not exposed to IFN-α2b before stimulation with insulin (t4 = 1.54 (P = 0.017), t8 = 1.75 (P = 0.019), t12 = 1.89 (P = NS)).
Several previous studies have demonstrated that in patients with chronic hepatitis C virus infection the antiviral efficacy of PEG-IFN/ribavirin combination therapy is reduced in the presence of insulin resistance.17-19 In addition, we have recently shown that in HCV patients with high homeostasis model of assessment, insulin resistance (HOMA-IR) at baseline, the impaired response to PEG-IFN can be demonstrated as early as 24 hours after the first injection of the drug, and is directly related to baseline insulin levels.20 The molecular mechanisms linking HCV infection and IR are complex and not yet fully understood. Insulin resistance may occur in HCV patients as a consequence of an associated classical form of metabolic syndrome, due to the high prevalence in the adult population of both conditions, which may therefore coexist. However, a large body of evidence has been obtained indicating that HCV exerts a synergistic effect on the development of IR. Initial studies suggested a role of tumor necrosis factor alpha (TNF-α), which is increased in HCV patients and may favor IR.30 Subsequently, evidence has been obtained indicating a potential direct involvement of some HCV proteins interfering with insulin signaling through the fine regulation of cellular effectors like SOCS.25, 31, 32 These findings led to the hypothesis that SOCS3 overexpression induced by HCV proteins in infected hepatocytes could be the common link between IR and reduced response to IFN signaling.
Here we aimed to explore the possibility of a direct and reciprocal interference between insulin and IFN signaling in human hepatocytes, independently of a role of HCV. Indeed, insulin pretreatment induced, in a dose-dependent manner, a significant reduction of intracellular PKR protein level and PKR, MxA, and OAS-1 gene expression, favoring the hypothesis that a state of hyperinsulinemia, as typically seen in HCV patients and IR, could reduce the response to IFN based therapy by interfering with signaling in infected hepatocytes.
Because insulin is known to induce SOCS3 overexpression34 and it is also known that SOCS3 inhibits IFN signaling,26, 33, 34 we investigated whether induction of SOCS3 by insulin could contribute to the inhibition of IFN-α signaling. However, although SOCS3 overexpression by insulin was observed, silencing of SOCS3 by siRNA did not restore IFN signaling. Although this effect was studied at the ISG mRNA level and ISG protein expression was not assessed, it seems reasonable to conclude that the inhibitory effect of insulin on IFN signaling is not mediated by SOCS3. On the other hand, in the present study, using the same cell line, we also investigated the effect of IFN-α on insulin signaling. Our data prove that IFN-α treatment is able to interfere with intracellular insulin signaling as shown by a dose-dependent reduction of insulin-mediated Ser 473 phosphorylation of Akt/PKB and the interference with insulin-mediated IRS-1 overexpression. It should be underlined here that our experiments identified reciprocal interference between interferon and insulin signaling in uninfected hepatocytes and it remains to be proven whether such effect is true also for HCV-infected cells, in which signal transduction could be quite different. Furthermore, the HepG2 cells we used were shown to express the TT genotype of IL28B, mimicking a situation in which activation of ISGs by exogenous interferon is somehow impaired. Further studies are warranted to explore whether signaling interference is true also for the more permissive IL28B CC-genotype.
It is well known that the major pathway for the generation of the antiviral response mediated by IFN involves a combination of different Jaks and Stats proteins to lead the transcription of ISGs.35-38 It has also been demonstrated that engagement of the “nonclassical” IFN signaling pathways may play an important complementary role in establishing the cellular antiviral state. This accessory pathway involved proteins such as IRS proteins and PI3-kinase, which typically mediate intracellular insulin signaling.39-42 Emerging evidence supports a key role for the PI3-kinase in IFN signaling for generation of the biological effects of IFNs,43 showing that the inhibition of PI3-kinase specific activity, using LY294002 inhibitor, reduces ISGs gene expression.
It was previously shown44 that hyperinsulinemia inhibits IFN-α-dependent activation of PI3-kinase through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of IRS-1 and the insulin-stimulated degradation of IRS-1 via the PI3-kinase pathway is a consequence of IRS-1 Ser312 phosphorylation.45, 46 Therefore, IFN-α-dependent IRS-1 tyrosine phosphorylation is impaired by serine IRS-1 phosphorylation due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for JAK1.47
These published data, together with our data showing that insulin-dependent SOCS3 overexpression does not impair IFN-α signaling on ISGs expression, suggest that insulin-mediated IRS-1 serine phosphorylation could be responsible for the interference with the “nonclassical” IFN signaling pathway resulting in a lower transcription of ISGs in insulin-treated cells (Fig. 8A). Less evident is the mechanism by which IFN-α could interfere with insulin signaling.
The IRS tyrosine phosphorylation plays critical roles in determining its activity and in promoting the insulin pathway.48, 49 A number of serine phosphorylation pathways have been identified to negatively interfere with the binding between IR and IRS and to decrease the insulin signaling leading to the IR condition,32, 50-52 but IFN-α does not seem to be able to lead to an IRS-1 serine phosphorylation.
The only published data on the effect of interferons on insulin signaling investigated the effect of IFN-γ in myogenic cells and adipocytes. IFN-γ-induced insulin resistance in myogenic cells was associated with decreased Akt/PKB phosphorylation and p70S6k, as well as with an augmented basal phosphorylation of p42MAPK. IFN-γ-mediated loss of insulin-stimulated glucose uptake in human adipocytes was coincident with reduced Akt/PKB phosphorylation and down-regulation of the IR, IRS-1, and GLUT4 that was mediated via sustained JAK-STAT1 pathway activation.53, 54
It is not known if a mechanism by which IFN-α interferes with insulin signaling in liver cells is similar to the ones described for IFN-γ in other cell types; however, the shared use of the IRS signaling pathway raises the possibility that the antagonism of IFN-α on insulin signaling could occur through the common use of proteins in the IRS signaling system (IRS-1 in particular) (Fig. 8B).
Although the validity of this hypothesis remains to be established, our results suggest a reciprocal interference between IFN-α and insulin signaling in liver cells. These findings may explain the increased frequency of insulin resistance seen in patients with chronic HCV infection and the reduced response to interferon-based therapy in these patients as the consequence of a vicious circle in which, during HCV infection, endogenous interferon and cytokines contribute to insulin resistance and the resulting hyperinsulinemia reduces the therapeutic response to exogenous alpha interferon. Termination of such a vicious circle could therefore be of paramount importance in the clinical management of chronic HCV infection.
- 3Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999; 6: 35-47.
- 19Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol 2005; 100: 1509-1515., , .Direct Link: