Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin ␤ B -subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma-derived cells and, synergistically with IL-6 and STAT-3 signaling, upregulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation. (Blood. 2012;120(2):431-439) IntroductionAnemia of inflammation develops as a complication of an acute or chronic activation of the immune response. It is particularly common in hospitalized patients and in the elderly and has a negative impact on recovery and survival. 1,2 Most chronic bacterial, fungal, viral, or parasitic infections with systemic manifestations can cause anemia of inflammation, as do rheumatologic disorders, systemic autoimmune disorders, inflammatory bowel disease, chronic kidney diseases, and some malignancies. 3 The limitation of iron supply to erythropoiesis is a major factor in the development of this anemia. Treatment includes administration of erythropoiesis-stimulating agents and intravenous iron. However, iron is rapidly trapped in the macrophage compartment, 4,5 rendering it unavailable for erythropoiesis once the initial iron bolus is incorporated into RBCs and body stores.Anemia of inflammation appears to be caused, at least in part, by the induction of the iron-regulatory hormone hepcidin. [6][7][8] Hepcidin acts by binding to the sole known iron-export channel, ferroportin, which is found on duodenal enterocytes, macrophages, and hepatocytes, the cell types that export iron into plasma. Binding of hepcidin to ferroportin induces its internalization and degradation, 9 which progressively inhibit iron efflux from these cells, leading to hypoferremia. The fundamental mechanisms causing increased hepcidin production by the liver during inflammation are still incompletely understood, but a cross-talk with the pathway through which hepcidin is regulated by iron is not excluded.Iron overload induces the expression of bone morphogenetic protein 6 (BMP6), a member of the TGF-␤ superfamily. Binding of BMP6 to paired serine/thr...

Gender-related disparities in the regulation of iron metabolism may contribute to the differences exhibited by men and women in the progression of chronic liver diseases associated with reduced hepcidin expression, e.g., chronic hepatitis C, alcoholic liver disease, or hereditary hemochromatosis. However, their mechanisms remain poorly understood. In this study we took advantage of the major differences in hepcidin expression and tissue iron loading observed between Bmp6-deficient male and female mice to investigate the mechanisms underlying this sexual dimorphism. We found that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective epidermal growth factor receptor (Egfr) inhibition by gefitinib (Iressa) in males markedly increases hepcidin expression. In males, where the suppressive effects of testosterone and Bmp6-deficiency on hepcidin expression are combined, hepcidin is more strongly repressed than in females and iron accumulates massively not only in the liver but also in the pancreas, heart, and kidneys. Conclusion: Testosterone-induced repression of hepcidin expression becomes functionally important during homeostatic stress from disorders that result in iron loading and/or reduced capacity for hepcidin synthesis. These findings suggest that novel therapeutic strategies targeting the testosterone/EGF/EGFR axis may be useful for inducing hepcidin expression in patients with iron overload and/or chronic liver diseases. (HEPATOLOGY 2014;59:683-694)