Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli.
Hepcidin, a key regulator of iron metabolism, is a small antimicrobial peptide produced by the liver that regulates intestinal iron absorption and iron recycling by macrophages. Hepcidin is stimulated when iron stores increase and during inflammation and, conversely, is inhibited by hypoxia and augmented erythropoiesis. In many pathologic situations, such as in the anemia of chronic disease (ACD) and iron-loading anemias, several of these factors may be present concomitantly and may generate opposing signaling to regulate hepcidin expression. Here, we address the question of dominance among the regulators of hepcidin expression. We show that erythropoiesis drive, stimulated by erythropoietin but not hypoxia, down-regulates hepcidin in a dose-dependent manner, even in the presence of lipopolysaccharide (LPS) or dietary iron-loading, which may act additively. These effects are mediated through down-regulation of phosphorylation of Stat3 triggered by LPS and of Smad1/5/8 induced by iron. In conclusion, hepcidin expression levels in the presence of opposing signaling are determined by the strength of the individual stimuli rather than by an absolute hierarchy among signaling pathways. Our findings also suggest that erythropoietic drive can inhibit both inflammatory and iron-sensing pathways, at least in part, via the suppression of STAT3 and SMAD4 signaling in vivo.
Huang
Hua
H
Centre de Recherche, Centre Hospitalier de l'Université de Montréal-Hôpital Nôtre-Dame, Montréal, QC, Canada.
Constante
Marco
M
Layoun
Antonio
A
Santos
Manuela M
MM
D018798:Anemia, Iron-Deficiency / Q000378:metabolism*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D064451:Hepcidins; D000860:Hypoxia / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D019266:Iron, Dietary / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051898:Smad1 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D019266:Iron, Dietary; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; C494087:Stat3 protein, mouse; D004921:Erythropoietin