Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice
Open accessAbstract
Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk.
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In subjects with a genetic predisposition, a shift of the microbiome towards colitogenic taxa by iron and disturbance of immune tolerance mechanisms may contribute to the manifestation of inflammatory bowel disease such as Crohn's disease and ulcerative colitis.
“In subjects with a genetic predisposition both, a shift of the microbiome towards colitogenic taxa by iron and the disturbance of immune tolerance mechanisms, may contribute to the manifestation of inflammatory bowel disease such as Crohn's disease and ulcerative colitis (Carrier et al., 2001(Carrier et al., , 2006;;Chua et al., 2013).”
From Iron in infection and immunity (2020) · cites this paper as Chua et al., 2013
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- Authors
- Chua, A. C. G., Klopcic, B. R. S., Ho, D. S., Fu, S. K., Forrest, C. H., Croft, K. D., Olynyk, J. K., Lawrance, I. C., & Trinder, D.
- Affiliations
- The University of Western Australia (AU)
- Murdoch University (AU)
- Corresponding author
- Chua, Anita C. G.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-11-06
- Volume
- 8
- Issue
- 11
- Pages
- e78850
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3819375
- OpenAlex
- W1980163672
- Cited by
- 76
- References
- 65
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 11 · 2014: 2
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- Murdoch University Research Portal (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eSpace (Curtin University) (submittedVersion, cc-by)
- Funders
- Raine Medical Research Foundation
- Gastroenterological Society of Australia
- Spinnaker Health Research Foundation
- Medical Research Council
- National Health and Medical Research Council (1007769, 1042370, 1020437)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- dietary iron, colorectal cancer, colonic inflammation, interleukin-6, interleukin-11, STAT3 signaling, macrophages, ferritin, iron transporters, DMT1, transferrin receptor 1, ferroportin, iron supplementation, inflammatory bowel disease, carcinogenesis, apoptosis
- MeSH terms
- Solute Carrier Family 11, Member 2, Animals, Colitis, Colonic Neoplasms, Enzyme-Linked Immunosorbent Assay, Female, Mice, Inbred C57BL, Phosphorylation, Receptors, Transferrin, Immunoblotting, Signal Transduction, Interleukin-6, Gene Expression Regulation, Neoplastic, Dextran Sulfate, Apoptosis, Interleukin-11, Iron, Dietary, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Cation Transport Proteins, Cell Proliferation, STAT3 Transcription Factor, Mice
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