Inflammation increases hepcidin expression by way of the Janus kinase (Jak)/STAT

signaling pathway, with the STAT3 transcription factor essential to this process.23, 26 Therefore, the ZD1839 possible role of STAT3 in the induction of hepcidin by IFN-α was investigated next. IFN-α treatment of Hep3b cells resulted in the rapid phosphorylation of STAT3 protein (Fig. 5B). STAT3 activation was critical to the hepcidin response to IFN-α, as siRNA-mediated knockdown of STAT3 expression (86% at the mRNA level; P < 0.0001 compared with control siRNA; Supporting Fig. 6) completely abolished hepcidin induction following IFN-α treatment (Fig. 5C). In agreement with these data, mutation of the STAT3 response element in the hepcidin promoter prevented the hepcidin response to IFN-α treatment (Fig. 5D). In keeping with other reports, crosstalk with the important bone morphogenetic protein (BMP) signaling pathway may play a contributory role in hepcidin induction by inflammation seen here.19 In this study we demonstrate an induction of hepcidin by IFN-α both in HCV patients and in cell culture, and a consequent plasma iron-reducing buy PCI-32765 effect of PEG-IFN-α therapy. Hepcidin is an acute phase protein, secreted in response to inflammatory stimuli, with increased hepcidin levels described in individuals with acute infection

or inflammation.27 Similar to the findings outlined in the current study, human volunteers given IL-6 or lipopolysaccharide (LPS) injections experienced increased serum hepcidin and rapid hypoferremia within hours of administration.22, 28 As mentioned above, systemic iron withdrawal in

this setting reflects an important innate immune response mechanism.12 An important finding of this study was the association between alterations in serum iron levels and the immediate viral response to PEG-IFN-α. The finding of significantly lower iron levels in patients with the greatest “first-phase” decline in HCV viral load was unexpected. Furthermore, serum iron levels at 24 hours were an independent predictor of the first phase viral decline (in HCV genotype 1 individuals), an indicator of future therapeutic outcome, and associated with both EVR and SVR. Similarly, serum ferritin rise during treatment medchemexpress has been previously identified as a positive predictor of SVR, possibly related to an induction by IFN-α.29 In this study, systemic iron withdrawal may simply represent a surrogate marker of PEG-IFN-α response, as the antiviral effect of PEG-IFN-α treatment overlaps with the iron-lowering function of hepcidin. Furthermore, peak serum hepcidin levels correlated significantly with that of IP-10, a marker of IFN response. Alternatively, it is tempting to speculate that the finding of hypoferremia associated with an enhanced PEG-IFN-α response might possibly reflect an antiviral mechanism of PEG-IFN-α action. Although the role of iron in viral infection remains unclear,30 iron reduction appears to improve HCV disease outcomes.