Interleukin-6 induces hepcidin expression through STAT3

Abstract

Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. Although hypoxia, erythroid demand, iron, and inflammation are all known to influence hepcidin expression, the mechanisms responsible are not well defined. In this report we show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). STAT3 is necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. Our findings provide a mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation. (Blood. 2006;108:3204-3209)

Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat

“…7 This study underlines the Iron regulation during acute-phase reaction N Sheikh et al differences between the two animal models and indirectly confirms that IL-6 is the major player in modifying iron metabolism under acute-phase condition. 13,[38][39][40][41][42][43][44] Most studies to date have shown that the transcriptional changes in the Hepc gene expression parallel the changes in serum iron concentration; however, limited studies have been performed to show the changes in the concentration of this important hormone in the serum. [45][46][47][48] Intramuscular TO injection induced significant decrease of the serum iron concentration without a significant change in serum proHepc concentration.…”

In vivo imaging of hepcidin promoter stimulation by iron and inflammation

“…Recent findings have provided information regarding the part of the promoter required for IL-6 to induce hepcidin expression through the mediation of STAT3 [11]. However, the mechanism by which iron stimulates hepcidin expression still remains unclear.…”

Saturated Fatty Acids Induce Post-transcriptional Regulation of HAMP mRNA via AU-rich Element-binding Protein, Human Antigen R (HuR)

“…2A, inset). Earlier studies concentrated on the regulation of HAMP expression at the transcriptional level (12)(13)(14)(15). The effect of fatty acids on HAMP transcription was examined by luciferase reporter assays in HepG2 cells transfected with pGL-3 Basic vector harboring the 1.5-kbp HAMP promoter (HAMP PromLuc).…”

“…Inflammatory cyto-kines, serum transferrin, erythropoiesis, and hepatic iron stores have all been shown to stimulate the promoter activities of both human and mouse hepcidin genes via the activation of specific transcription factors (12)(13)(14)(15). It should, however, be noted that other iron-regulatory proteins, transferrin receptor 1 and ferritin, are regulated at the post-transcriptional and translational level, respectively, by iron-regulatory RNA-binding proteins (IRPs), IRP1 and IRP2 (16).…”