Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs

UCLA Department of Medicine, 10833 Le Conte Ave, CHS 37-131, Los Angeles, CA 90095, USA.
Blood (Impact Factor: 10.45). 10/2005; 106(6):2196-9. DOI: 10.1182/blood-2005-04-1766
Source: PubMed


Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse. A single intraperitoneal injection of hepcidin caused a rapid fall of serum iron in a dose-dependent manner, with a 50-microg dose resulting in iron levels 80% lower than in control mice. The full effect was seen within only 1 hour, consistent with a blockade of iron export from tissue stores and from macrophages involved in iron recycling. Serum iron remained suppressed for more than 48 hours after injection. Using radiolabeled hepcidin, we demonstrated that the serum concentration of hepcidin at the 50-microg dose was 1.4 microM, consistent with the inhibitory concentration of 50% (IC50) of hepcidin measured in vitro. Radiolabeled hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum. Our study highlights the central role of the hepcidin-ferroportin interaction in iron homeostasis. The rapid and sustained action of a single dose of hepcidin makes it an appealing agent for the prevention of iron accumulation in hereditary hemochromatosis.

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    • "A second method is chemical synthesis of hepcidin, which requires various refolding procedures. In addition, synthetized hepcidin molecules have different sizes that may interfere with hepcidin function (Rivera et al. 2005). "
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    ABSTRACT: Hepcidin is the primary regulatory hormone responsible for lowering the iron content in the blood circulation. Due to its biodegradability and low cytotoxicity, hepcidin is considered as an alternative for iron chelators. The baculovirus expression system may be suitable for human hepcidin production because the expressed proteins generally exhibit proper folding, post-translational modifications, and oligomerization. Using data from two vector maps, pFastBac1 and pFastBac HTB, a unique vector was designed encoding human hepcidin-25 as fusion recombinant peptide. Expression analysis showed that it was expressed as a peptide with a molecular weight near to 5 kDa. After purification and TEV treatment, findings revealed that recombinant human hepcidin-25 was functional and its effect was dose dependent (P=0.001). It was concluded that baculovirus expression was a suitable expression system for production of functional recombinant human hepcidin-25.
    Brazilian Archives of Biology and Technology 01/2015; 1(1):90-95. DOI:10.1590/S1516-8913201400018 · 0.55 Impact Factor
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    • "Hepcidin is a master regulator of iron homoeostasis in humans and other mammals [46]. It inhibits the absorption of iron in the small intestine and the release of recycled iron from macrophages, effectively decreasing the delivery of iron to maturing erythrocytes in the bone marrow [47]. In this regard, IL-6 is known to induce hepcidin production in liver cells [48]. "
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    ABSTRACT: Pro-inflammatory cytokines play a major role in the initiation and maintenance of joint inflammation and destruction in rheumatoid arthritis (RA). The therapeutic success of biologics targeting tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin (IL)-6 receptor (IL-6R) has broadened the treatment options for RA. These agents have potential overlapping and discriminating biologic effects, as well as different pharmacological features. Tocilizumab (TCZ) is a humanized monoclonal antibody that binds and neutralizes IL-6R, resulting in the inhibition of various IL-6-mediated biological activities, including inflammation-related, immunomodulatory and tissue/matrix remodelling effects. Randomized, double-blind, controlled phase III studies and a number of early clinical observational studies have shown that treatment with TCZ results in rapid and sustained improvement in the signs and symptoms of RA among different patient populations. These studies have established the efficacy and safety of TCZ. Here, we review the pleiotropic functions of IL-6 and how it impinges on many aspects of RA pathogenesis, and highlight the clinical experience to date with TCZ as an emerging new treatment option for RA.
    International Reviews Of Immunology 08/2014; 34(3). DOI:10.3109/08830185.2014.938325 · 4.10 Impact Factor
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    • "Short- and long-term hepcidin injections, or hepatic over-expression of hepcidin transgene in Hfe-deficient mice resulted in successful reconstitution of hepcidin expression to the levels present in wild type mice. Furthermore, high plasma iron levels present in Hfe-/- mice were significantly reduced by hepcidin treatments, without affecting hepatic iron load which remained inappropriately high in regard to hepcidin levels (Nicolas et al., 2003; Laftah et al., 2004; Rivera et al., 2005; Viatte et al., 2006; Moran-Jimenez et al., 2010). Neither has exogenous Bmp6 administration to Hfe-/- mice succeeded to reduce hepatic iron burden, although hepcidin expression was restored to the levels present in wild type mice, followed by a significant drop in serum iron levels and redistribution of iron in the spleen and duodenum in Hfe-/- mice (Corradini et al., 2010). "
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    ABSTRACT: Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.
    Frontiers in Pharmacology 03/2014; 5:42. DOI:10.3389/fphar.2014.00042 · 3.80 Impact Factor
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