Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice

Abstract

Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidinmediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-α transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.

Effect of ferroportin polymorphism on iron homeostasis and infection

“…With the internalization and subsequent degradation of FPN by lysosomes triggered by hepcidin binding, iron accumulates in the macrophages and this is followed by increased intracellular H-ferritin synthesis in order to safely store the iron [36]. It is generally understood that hepcidin has no effect on the expression of FPN mRNA [37] but recent data from animal experiments seem to suggest that hepcidin does mediate transcription of FPN gene [38].…”

Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients

“…In experimental settings, pre-treatment with intravenous hepcidin or the induction of hepatic hepcidin expression prevents the inflammatory response due to exposure to lipopolysaccharide. Pagani et al [4] suggested that the inverse relationship between the levels of proinflammatory markers and circulating hepcidin may result from the anti-inflammatory properties of the latter [5] . Iron is essential not only for erythropoiesis but also for several bioenergetic processes in skeletal muscle.…”

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

“…The regulation of hepcidin synthesis occurs through several mechanisms such as hypoxia, inflammation and endoplasmic reticulum stress, the concentration of serum iron, and increased erythropoiesis [40,41]. …”