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Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes
- Source :
- PLoS ONE, Vol 16, Iss 6, p e0253475 (2021), PLoS ONE
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP, ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.
- Subjects :
- Cell signaling
Bone Morphogenetic Protein 6
Ferroportin
Siderophores
Smad Proteins
SMAD
Signal transduction
Biochemistry
Mice
Mathematical and Statistical Techniques
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
SOCS3
Post-Translational Modification
Phosphorylation
Cultured Tumor Cells
0303 health sciences
Multidisciplinary
biology
Chemistry
Statistics
Cell biology
STAT signaling
Bone morphogenetic protein 6
Liver
030220 oncology & carcinogenesis
Physical Sciences
Medicine
Biological Cultures
HAMP
Cellular Types
Anatomy
Research Article
STAT3 Transcription Factor
Signal Inhibition
Iron Overload
SMAD signaling
Science
Deferoxamine
Research and Analysis Methods
03 medical and health sciences
Hepcidins
Hepcidin
Cell Line, Tumor
Animals
Humans
Statistical Methods
030304 developmental biology
Ferritin
Analysis of Variance
Interleukin-6
Biology and Life Sciences
Proteins
Protein Complexes
Cell Biology
Cell Cultures
Hepatocytes
biology.protein
Hepatoma Cells
Mathematics
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 16
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....fa62d8e0a3966f4bcac03ebb23198488