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

• Published in: PloS one Vol. 8; no. 11; p. e78850
• Main Authors: Chua, Anita C G, Klopcic, Borut R S, Ho, Desiree S, Fu, S Kristine, Forrest, Cynthia H, Croft, Kevin D, Olynyk, John K, Lawrance, Ian C, Trinder, Debbie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.11.2013; Public Library of Science (PLoS)
• Subjects: Anemia; Animals; Apoptosis; Apoptosis - drug effects; Azoxymethane; Cancer; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell proliferation; Cell Proliferation - drug effects; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonoscopy; Colorectal cancer; Colorectal carcinoma; Comparative analysis; Cytokines; Dextran; Dextran Sulfate - toxicity; Dextrans; Diet; Dietary supplements; Divalent metal transporter-1; Drinking water; Endoscopy; Enzyme-Linked Immunosorbent Assay; Epithelial cells; Female; Ferritin; Gastroenterology; Gastrointestinal diseases; Gene expression; Gene Expression Regulation, Neoplastic; Health aspects; Health risks; Histology; Homeostasis; Hospitals; Immunoblotting; In Situ Nick-End Labeling; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 11; Interleukin 6; Interleukin-11 - genetics; Interleukin-11 - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Intestine; Iron; Iron, Dietary - adverse effects; Macrophages; Medical research; Medicine; Mice; Mice, Inbred C57BL; Mucosa; Oxidative stress; Pharmacology; Phosphorylation; Phosphorylation - drug effects; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal Transduction; Signaling; Sodium; Sodium sulfate; Stat3 protein; STAT3 Transcription Factor - metabolism; Studies; Sulfates; Transferrin; Tumor necrosis factor-TNF; Tumorigenesis; Tumors; Australia; Western Australia Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078850

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.