Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice.
Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice.
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DOI：
10.1371/journal.pone.0078850
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Trinder D
中科院分区：
文献类型：
--
作者：
Chua AC;Klopcic BR;Ho DS;Fu SK;Forrest CH;Croft KD;Olynyk JK;Lawrance IC;Trinder D
慢性肠道炎症和高膳食铁与结直肠癌的发展有关。在炎症相关结肠直肠癌小鼠模型中研究了Stat 3活化在铁诱导的结肠炎症和肿瘤发生中的作用。小鼠，无论是铁补充或控制饮食喂养，处理与氧化偶氮甲烷和葡聚糖硫酸钠（DSS）。通过内窥镜和组织学评估肠道炎症和肿瘤发展，通过实时PCR评估基因表达，通过免疫印迹评估Stat 3磷酸化，通过ELISA评估细胞因子，通过TUNEL分析评估细胞凋亡。与DSS治疗后一周的对照饮食相比，喂食铁补充的小鼠的结肠炎症更严重，结肠IL-6和IL-11释放和Stat 3磷酸化增强。IL-6和铁蛋白（铁储存蛋白）与巨噬细胞共定位，表明铁可能直接作用于产生IL-6的巨噬细胞。铁增加DSS诱导的结肠上皮细胞增殖和凋亡与增强的粘膜损伤一致。DSS处理的小鼠出现贫血，通过膳食补铁不能缓解。DSS治疗后六周，与对照小鼠相比，补充铁的小鼠发展出更多更大的结肠肿瘤。DSS治疗的小鼠肿瘤内IL-6和IL-11表达增加，并且IL-6和可能的IL-11被膳食铁增强。结肠肿瘤中铁输入者，二价金属转运蛋白1和转铁蛋白受体1的基因表达增加，铁输出者，铁转运蛋白的基因表达减少，提示铁摄取增加。膳食铁和结肠炎症协同激活结肠IL-6/IL-11-Stat 3信号传导促进肿瘤发生。口服铁剂治疗可能对炎症性肠病有害，因为它可能会加剧结肠炎症并增加结直肠癌的风险。
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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影响因子：
24.5
作者：
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通讯作者：
Tselepis, C.
影响因子：
25.7
作者：
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