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.
Highlights
Inflammatory bowel diseases (IBD) are life-long incurable conditions that are increasing in frequency[1] with high morbidity including an increased risk for colorectal cancer (CRC).[2]
Colonic tumor necrosis factor (TNF) mRNA expression was increased in both Iron/dextran sodium sulfate (DSS) and Control/DSS mice (Table 3; P,0.05) compared with non-DSS treated mice whilst interferon c (IFNc) expression was increased in Iron/DSS mice (P = 0.001) with a trend to increase in Control/DSS mice
There was an increase in mRNA expression of IL-11 (P,0.05) but not oncostatin M and ciliary neutrophic factor, which are all members of the IL-6 family of cytokines, in Iron/DSS mice compared with Iron mice
Summary
Inflammatory bowel diseases (IBD) are life-long incurable conditions that are increasing in frequency[1] with high morbidity including an increased risk for colorectal cancer (CRC).[2]. Whilst the pathogenesis of IBD associated-CRC is unclear, chronic inflammation is thought to be a significant contributor.[3] Intestinal inflammation can result in abdominal pain, intestinal bleeding and diarrhea, and many IBD patients suffer systemic symptoms of malnutrition and anemia. Anemia is the most common systemic complication of IBD[4] and iron deficiency is evident in many IBD patients.[5,6]. Chronic intestinal inflammation in IBD results in the upregulation of pro-inflammatory cytokines causing damage to the intestinal mucosa resulting in recurrent intestinal blood loss and anemia.[7] These cytokines contribute to anemia of inflammation,[7,8] a condition where inflammation causes dysregulation of iron metabolism and inhibition of erythropoiesis. The inflammatory cytokine interleukin (IL)-6 increases the synthesis of liver hepcidin, a major iron-regulatory hormone central to iron homeostasis, resulting in reduced duodenal iron absorption and retention of iron in macrophages and hepatocytes promoting iron storage limiting the availability of iron for erythropoiesis.[9]
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