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Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli
- Publication Year :
- 2009
-
Abstract
- 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 phosporylation 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.
- Subjects :
- Lipopolysaccharides
STAT3 Transcription Factor
Smad5 Protein
medicine.medical_specialty
Immunology
Inflammation
Biochemistry
Article
Smad1 Protein
Mice
Hepcidins
Hepcidin
Internal medicine
hemic and lymphatic diseases
medicine
Animals
Erythropoiesis
Phosphorylation
STAT3
Hypoxia
Erythropoietin
Smad4 Protein
biology
Anemia, Iron-Deficiency
Interleukin-6
Cell Biology
Hematology
Hypoxia (medical)
medicine.disease
Mice, Inbred C57BL
Endocrinology
Smad8 Protein
biology.protein
Female
medicine.symptom
Signal transduction
Iron, Dietary
Anemia of chronic disease
medicine.drug
Antimicrobial Cationic Peptides
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....c9a099a0ff6fdd61ab6d4eb2a04d23b5