Hepcidin: inflammation's iron curtain.

Editorial Hepcidin: inflammation's iron curtain Rheumatologists and their patients are the beneficiaries of a recently identified peptide, hepcidin (Table 1). Isolated from human urine and plasma in the year 2000 [1, 2], hepcidin appears to be the long-sought iron-regulatory hormone responsible for the anaemia of chronic disease [3, 4]. It is more than that: it is an acute-phase reactant, responding to infection and inflammation [5]; it is an antimicrobial peptide that disrupts microbial membranes [1, 6]; and it provides an iron-restricted internal milieu inhospitable to microbes [7, 8]. Hepcidin is a 25 amino acid, 2–3 kDa, cationic peptide that has broad antibacterial and antifungal actions [1]. In concert with other antimicrobial peptides, known as defensins and cathelicidins [9], it provides a first line of defence at mucosal barriers [1, 2]. However, more germane for rheumatologists is its control of iron kinetics. Produced by hepatocytes, hepcidin inhibits the intestinal absorption [1, 10], macrophage release [3, 7] and placental passage [10] of iron. Hepcidin mRNA moves with the body's iron levels, increasing as they increase and decreasing as they decrease [11]. More pertinently, hepcidin rises with infection or inflammation and falls with hypoxia or anaemia [12]. The anaemia of chronic disease has long confounded physicians. It is generally normocytic and normochromic, but may be hypo-chromic or microcytic [13]. The low serum iron and normal-to-low iron-binding capacity, in conjunction with a high-to-normal serum ferritin level in patients with inflammatory disease, has been perplexing. Also notable has been the shortened red blood cell survival and blunted erythropoietin-induced production of red blood cells. At one time known as the anaemia of infection, it became known, after man's entry into the age of antibiotics, as the anaemia of chronic disease, and now, perhaps more aptly, it is the anaemia of inflammation. Iron can be toxic. It catalyses the generation of reactive free radicals [14] and activates NF-B, the prototypic transcription factor for genes involved in inflammation [15]. At high levels, iron is damaging to tissues. Humans need little dietary iron, 1–2 mg a day sufficing for the average adult male [16]. However, mammals lack a regulated pathway for iron excretion [12], so iron absorption has to be tightly regulated. Hepcidin acts as a negative regulator of iron absorption: USF2 knockout mice lacking hepcidin mRNA become iron-overloaded [17]; transgenic mice with increased hepcidin expression die at birth with severe iron deficiency [10]; humans with hepcidin-producing adenomas develop …