Comment on Wrighting and Andrews, page
The inflammatory cytokine IL-6 directly regulates hepcidin through induction and subsequent promoter binding of STAT3. Clarification of the mechanism regulating hepcidin may allow the development of innovative therapeutic interventions for clinical conditions of abnormal iron homeostasis.
Hepcidin is a circulating hormone that plays a central role in iron homeostasis. Increased hepcidin production associated with excess iron or inflammation inhibits iron absorption and iron recycling from macrophages. Conversely, iron deficiency and genetic hemochromatosis are associated with decreased hepcidin production, resulting in increased iron absorption and recycling. The mechanisms regulating hepcidin expression remained largely unknown. Recent studies have shown that a bone morphogenetic protein BMP/SMAD signaling cascade is important for basal regulation of hepcidin transcription.1,2 Although that pathway clarifies the role of hemojuvelin in hepcidin regulation, it does not account for the induction of hepcidin expression in inflammation.
One of the important mediators of inflammation is the cytokine interleukin-6 (IL-6). Upon an inflammatory stimulus, IL-6 is released and binds to a complex of the IL-6 receptor α and gp130. The IL-6 ligand receptor interaction results in the activation of Janus kinases (JAKs) that phosphorylate signal transducers and activators of transcription (STAT) proteins, predominantly STAT3 (see figure). Upon phosphorylation at tyrosine residue 705, STAT3 translocates into the nucleus, where it regulates the transcription of many target genes.3 IL-6 treatment stimulates hepcidin expression in isolated hepatocytes, and administration of IL-6 to human subjects stimulates hepcidin production and results in low serum iron (hypoferremia) in vivo.FIG1
IL-6 binds to a complex of the IL-6 receptor α and gp130. This results in the activation of Janus kinases (JAKs) that phosphorylate signal transducer and activator of transcription 3 (STAT3). Upon phosphorylation, STAT3 dimers are formed through phosphoYXXQ motifs (Y) and translocate into the nucleus where they regulate hepcidin transcription. Adapted with permission from Heinrich et al3 (Fig1); copyright 2003 The Biochemical Society.
IL-6 binds to a complex of the IL-6 receptor α and gp130. This results in the activation of Janus kinases (JAKs) that phosphorylate signal transducer and activator of transcription 3 (STAT3). Upon phosphorylation, STAT3 dimers are formed through phosphoYXXQ motifs (Y) and translocate into the nucleus where they regulate hepcidin transcription. Adapted with permission from Heinrich et al3 (Fig1); copyright 2003 The Biochemical Society.
In their study in this issue, Wrighting and Andrews intended to clarify the role of IL-6 in the stimulation of hepcidin production associated with inflammation by determining whether IL-6 acts directly to up-regulate hepcidin expression and by elucidating the downstream mechanism of IL-6–mediated hepcidin induction. In a series of elegant experiments, the authors have identified an IL-6–responsive element in the putative hepcidin promoter; demonstrated that IL-6 regulates hepcidin expression through direct binding of STAT3 to the promoter; and, finally, demonstrated that STAT3 is necessary and sufficient to confer IL-6 responsiveness. These observations not only illuminate IL-6 regulation of hepcidin but also suggest that, even in the absence of elevated cytokine levels, aberrations in hepatic STAT3 regulation could lead to increased hepcidin and anemia.
Collectively, these studies indicate the existence of at least 2 signaling pathways involved in the transcriptional regulation of hepcidin: the BMP/SMAD signaling of hemojuvelin and the IL-6/STAT3 signaling of inflammation. This impressive advance in our current understanding implies that, with further progress in this line of research, new pharmacologic approaches could eventually be developed for innovative therapeutic interventions in clinical conditions of abnormal iron homeostasis. ▪
