Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells

Cannon Research Center, Carolinas Medical Center, Charlotte, NC 28203, United States.
World Journal of Gastroenterology (Impact Factor: 2.37). 09/2009; 15(36):4499-510. DOI: 10.3748/wjg.15.4499
Source: PubMed


To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins.
Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots.
Iron, in the form of ferric nitrilotriacetate, increased oxidative stress and up-regulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOX1. Silencing the up-regulation of HMOX1 nuclear factor-erythroid 2-related factor 2 (Nrf2) by Nrf2-siRNA decreased FeNTA-mediated up-regulation of HMOX1 mRNA levels. These iron effects were completely blocked by deferoxamine (DFO). Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them.
Excess iron up-regulates HMOX1 and down-regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection.

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    • "We have previously shown that heme oxygenase-1 (HO-1), a pivotal cytoprotective gene, can be induced to inhibit HIV-1, West Nile virus, dengue, and Leishmania donovani infection of human monocyte-derived macrophages (MDM) [1] [2] [3] [4] [5]. HO-1 induction has also been reported to suppress hepatitis B virus, hepatitis C virus, and malaria infections [6] [7] [8] [9] [10], Recently, Hill-Batorski et al. reported HO-1-dependent suppression of Ebola virus replication [11], further establishing a key role for this endogenous enzyme in host defense. "
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    Biochemical and Biophysical Research Communications 10/2014; 454(1). DOI:10.1016/j.bbrc.2014.10.035 · 2.30 Impact Factor
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    • "Several studies indicate that HO-1 induction or overexpression in replicons inhibit HCV replication [14], [15], while others have specified that it might be the products of the reaction catalyzed by HO-1 that are responsible for this process. It has been demonstrated that both iron and biliverdin display antiviral activity [24]–[27]. However, on the contrary, Kakizaki et al [28] note that iron enhances hepatitis C virus replication in cultured human hepatocytes. "
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    PLoS ONE 04/2014; 9(4):e95564. DOI:10.1371/journal.pone.0095564 · 3.23 Impact Factor
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    • "BV Type I interferon induction Lehmann et al. (2010) Heme Anti-NS3/4A protease Zhu et al. (2010a) Heme HO-1 induction Shan et al. (2007), Zhu et al. (2008) ZnMP HO-1 induction and Bach 1 inhibition Hou et al. (2008) ZnMP Ubiquitination of NS5A Hou et al. (2010) Fe Antipolymerase Fillebeen et al. (2005) Fe Decreased HCV replication Yuasa et al. (2006), Zhu et al. (2010a) Fe HO-1 induction Hou et al. (2009) Zn Decreased viral replication Yuasa et al. (2006) HO-1 enzyme Enzyme overexpression Zhu et al. (2008) HBV Heme Anti-reverse transcriptase Lin and Hu (2008) HO-1 induction Protzer et al. (2007) HIV BV/BR Anti-HIV protease McPhee et al. (1996) Synthetic porphyrins Anti-HIV protease Decamp et al. (1992) Heme/MPs Anti-reverse transcriptase Levere et al. (1991), Staudinger et al. (1996), Argyris et al. (1999) HO-1 induction HO-1 induction Devadas and Dhawan (2006) MPs Gp120 inhibition Song et al. (1997) multiple viral target sites on different viruses indicates that these compounds would be also useful for patients with dual or even triple infections. Co-infected patients are a serious problem worldwide and invariably present with more severe medical disease, aggressive hepatitis, and a number of treatment dilemmas (den Brinker et al., 2000; Koziel and Peters, 2007; Zhou et al., 2011). "
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