Hepcidin: a molecular link between inflammation and anaemia

Abstract

Hepcidin is a small, cysteine-rich cationic peptide that was purified only recently from human urine and plasma ultrafiltrate [1,2]. It forms a short hairpin with the two arms linked by four disulfide bridges in a ladder-like fashion. One of the disulfide bridges lies between two adjacent cysteine residues near the turn of the hairpin. The peptide appears to be conserved among species, and, due to its unusual disulfide motifs, it may represent a new class of antimicrobial peptides [3]. In mice, hepcidin mRNA was found to be induced by iron overload as well as by treatment with lipopolysaccharide [4]. Hence, a role in iron homeostasis and acute phase response was suggested. Nicolas et al. [5] submitted the idea that hepcidin constitutes a humoral factor regulating intestinal iron absorption and iron storage in macrophages. Because loss of hepatic hepcidin expression in a murine knockout model led to visceral iron overload, increments of non-transferrin-bound iron and a decrease of splenic iron load [5], Fleming and Sly [6] proposed that an elevated expression of hepcidin should result in features commonly encountered during the anaemia of inflammation, namely a decrease of circulating iron, an increase of iron within cells of the reticuloendothelial system (RES) and a reduced intestinal iron absorption. Nicolas et al. [7] found that the gene encoding hepcidin is regulated in response to anaemia, hypoxia and inflammation: Acute haemolysis induced by phenylhydrazine and blood loss following repeated phlebotomies dramatically decreased hepatic hepcidin mRNA expression, even after increasing hepatic hepcidin mRNA expression to high levels by iron loading [4,7]. Hypoxia (2% oxygen) specifically downregulated hepcidin transcription in hepatoma cells, and the same response was observed in mice that were kept in hypobaric hypoxia chambers [7]. Induction of an acute inflammatory response by a single turpentine injection resulted in a 2-fold reduction of serum iron in wild-type mice but, importantly, not in hepcidin-deficient mice [7]. In a murine model of chronic inflammation (three repeated turpentine injections within 4 weeks), hepatic hepcidin mRNA increased 6-fold in comparison with saline-treated animals, and red blood cell parameters and serum iron levels decreased [7]. These results strongly suggest that hepcidin exerts an inhibitory effect on iron absorption by duodenal enterocytes and, possibly, on iron release from the RES [7].