Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice.

Abstract

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.

• Authors: Anita C G Chua, Borut R S Klopcic, Desiree S Ho, S Kristine Fu, Cynthia H Forrest, Kevin D Croft, John K Olynyk, Ian C Lawrance, Debbie Trinder
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e78850 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24223168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cation Transport Proteins
• Interleukin-11
• Interleukin-6
• Iron, Dietary
• Receptors, Transferrin
• STAT3 Transcription Factor
• Tfrc protein, mouse
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
• Dextran Sulfate

Topics

• Animals
• Apoptosis (drug effects)
• Cation Transport Proteins (genetics, metabolism)
• Cell Proliferation (drug effects)
• Colitis (chemically induced, genetics, metabolism)
• Colonic Neoplasms (genetics, metabolism)
• Dextran Sulfate (toxicity)
• Enzyme-Linked Immunosorbent Assay
• Female
• Gene Expression Regulation, Neoplastic
• Immunoblotting
• In Situ Nick-End Labeling
• Interleukin-11 (genetics, metabolism)
• Interleukin-6 (genetics, metabolism)
• Iron, Dietary (adverse effects)
• Mice
• Mice, Inbred C57BL
• Phosphorylation (drug effects)
• Receptors, Transferrin (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (metabolism)
• Signal Transduction