In agreement with our observation, an in vitro study by Miura et 

In agreement with our observation, an in vitro study by Miura et al. using hepatoma cells showed that HCV-induced ROS inhibited the binding activity of C/EBPα to the hepcidin promoter through increased histone deacetylase activity.[43] Hepcidin is also regulated by both circulating transferrin-bound iron and intracellular iron stores. The exact mechanism is still unknown but seems to involve the BMP/SMAD pathway. As yet, there is no convincing evidence that accounts for the suppressive

transcription of hepcidin through the BMP/SMAD cascade in chronic hepatitis C. Taking into account the significant correlation between hepcidin and serum ferritin, or the histological iron score, hepcidin transcription seems to be properly regulated in response to the iron concentration in chronic hepatitis C. Thus, the opposing effects of HCV-induced PD-0332991 concentration hepcidin-suppressive factors and iron load-induced hepcidin-stimulation factors potentially regulate hepcidin transcription in chronic hepatitis C. As suggested by Girelli et al.,[39] in the early phase of chronic hepatitis C hepcidin may be prominently suppressed by HCV, but as iron accumulates, Ivacaftor manufacturer the negative influence of viral factors may be masked by the positive stimulation of iron. Inflammation also regulates hepcidin

transcription. Pro-inflammatory cytokines such as IL-6 mediate this response by inducing medchemexpress transcription of hepcidin mRNA via STAT3, which binds to a STAT-responsive element within the hepcidin promoter.[24, 25] Our transgenic mice expressing the HCV polyprotein did not show any inflammation in the liver. A possible pitfall in this experimental model was that we could not take the inflammatory effect on hepcidin regulation into account, which is different from what is observed

in patients with chronic hepatitis C. Serum levels of IL-6 have been shown to be elevated in patients with HCV-related chronic liver disease,[44] which raises the possibility that IL-6 acts to stimulate hepcidin expression through the STAT3 pathway. This would be expected to counteract the decrease in hepcidin transcription caused by HCV-induced ROS. However, no significant relationship has been found between serum IL-6 and hepcidin in patients with chronic hepatitis C,[39, 45] even though a paracrine effect of local IL-6 release on hepcidin transcription in the liver cannot be excluded. On the other hand, chronic inflammation with production of pro-inflammatory cytokines has the potential to deliver an additional burden of ROS, which would be expected to reinforce the decrease in hepcidin transcription. Most likely, during chronic inflammation states in vivo like chronic hepatitis C, the regulation of hepcidin is more complex and may depend on many variables, including the particular stage of systemic and/or hepatic inflammatory disease.

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