STAT3 Is Required for IL-6-gp130–Dependent Activation of Hepcidin In Vivo
Open accessAbstract
Background & aims Hepcidin is a peptide hormone that is central to the regulation of iron homeostasis. In response to interleukin 6 (IL-6), hepatocytes produce hepcidin that decreases iron release/transfer from enterocytes and macrophages and causes hypoferremia. To clarify the molecular pathways involved in hepcidin activation by IL-6, we used different mice strains in which the main IL-6/gp130 signaling pathways have been genetically disrupted. Methods We generated mice with hepatocyte-specific deletion of the IL-6 signal-transducing gp130 receptor (alfpgp130 (LoxP/LoxP)), with a gp130 receptor lacking the essential region for STAT1 and -3 activation (alfpCre gp130(DeltaSTAT/LoxP)) or mice expressing a gp130 allele lacking the essential tyrosine for RAS-MAPK activation (alfpCregp130(Y757F/LoxP)). We studied gp130-dependent pathways and hepcidin mRNA expression by Western blot, reverse-transcription polymerase chain reaction, and Northern blot in vivo and ex vivo. Results IL-6 stimulated phospho STAT3, serum amyloid A (SAA), and suppressor of cytokine signaling 3 (SOCS3) expression in livers of wild-type and alfpCregp130(Y757F/LoxP) mice, whereas this response was blocked in alfpCre gp130(LoxP/LoxP) and alfpCre gp130(DeltaSTAT/LoxP) mice. In wild-type and alfpCregp130(Y757F/LoxP) animals, significantly higher hepcidin mRNA expression was found 3 to 6 hours after IL-6 stimulation. In contrast, no IL-6-dependent regulation of hepcidin mRNA expression was found in alfpgp130 (DeltaSTAT/LoxP) and AlfpCre gp130 (LoxP/LoxP) animals. In primary hepatocytes, higher hepcidin mRNA expression after IL-6 stimulation was only observed when gp130-STAT3-dependent signaling was intact. Conclusions We have demonstrated that both in vivo and in vitro STAT3 is the key transcription factor responsible for IL-6 activation of hepcidin gene expression in the liver.
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IL-6 mediates these effects directly because it activates STAT3 to bind to the HAMP promoter, thus stimulating HAMP expression.
“IL-6 mediates these effects directly because it activates STAT3 to bind e.g. to the HAMP promoter, thus stimulating HAMP expression (Pietrangelo et al., 2007;Wrighting and Andrews, 2006).”
From Iron in infection and immunity (2020) · cites this paper as Pietrangelo et al., 2007
The Discussion (page unavailable) identifies STAT3 as a key factor in IL-6-induced hepcidin transcription, and the paper reports STAT3 activation after IL-6 stimulation. It does not establish that STAT3 directly binds the HAMP promoter; it cites a separate promoter-fragment study and says the interplay of factors at the promoter remains unclear. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMost microbial infections raise IL-6 early; IL-6 then drives hepcidin transcription through JAK2-STAT3, requiring STAT3-binding sites in the HAMP promoter.
“IL-6 is increased early in most microbial infections and it stimulates hepcidin transcription via the JAK2–STAT3 pathway in a manner dependent on STAT3-binding motifs in the promoter of HAMP (the hepcidin gene)89–91.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [91]
STAT3 is a positive effector of hepcidin expression, and ROSs inhibit this effect, creating a link between ROSs and Fe metabolism.
“STAT3 is another positive effector of hepcidin expression [347,348], and ROSs inhibit this effect [349], thereby creating a link between ROSs and Fe metabolism.”
The inflammatory increase in hepcidin is mainly caused by increased IL-6, which induces hepcidin gene transcription through the JAK2/STAT3 pathway.
“The inflammatory increase in hepcidin is mainly caused by increased concentrations of IL-6 (interleukin-6) [19], inducing the transcription of the hepcidin gene through the JAK2/STAT3 [20][21][22] pathway.”
From Iron and infection (2018) · cites this paper as [20]
In nonintestinal cells, circulating iron is bound to transferrin and imported via receptor-mediated endocytosis after binding to the transferrin receptor.
“In nonintestinal cells, circulating iron is bound to transferrin (Tf) and is imported via receptor-mediated endocytosis after binding to the transferrin receptor (TfR) (249).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [249]
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- Authors
- Pietrangelo, A., Dierssen, U., Valli, L., Garuti, C., Rump, A., Corradini, E., Ernst, M., Klein, C., & Trautwein, C.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- Universitätsklinikum Aachen (DE)
- Ludwig Cancer Research (BE)
- Corresponding author
- Trautwein, Christian
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2007-01
- Volume
- 132
- Issue
- 1
- Pages
- 294-300
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2046878952
- Cited by
- 315
- References
- 43
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 9 · 2021: 15 · 2020: 14 · 2019: 13 · 2018: 17 · 2017: 23 · 2016: 18 · 2015: 16 · 2014: 25 · 2013: 25 · 2012: 19
- FWCI
- 11.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- hepcidin, STAT3, interleukin-6, gp130, iron homeostasis, hepatocytes, SOCS3, serum amyloid A, RAS/MAPK pathway, liver, hypoferremia, primary hepatocytes
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Iron, Mice, Mutant Strains, Phosphorylation, RNA, Messenger, Transcription, Genetic, Signal Transduction, Interleukin-6, Hepatocytes, Antimicrobial Cationic Peptides, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice, Hepcidins
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