Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6.
Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6.
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DOI：
10.1016/j.taap.2014.07.001
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发表时间：
2014-09
影响因子：
3.8
通讯作者：
Hai-lei Zhao;Xinhua Zhang;Xuewei Chen;Y. Li;Zun-qiong Ke;T. Tang;Hongyan Chai;Austin M Guo;
中科院分区：
文献类型：
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作者：
Hai-lei Zhao;Xinhua Zhang;Xuewei Chen;Y. Li;Zun-qiong Ke;T. Tang;Hongyan Chai;Austin M Guo;
M2巨噬细胞极化与结直肠癌的发展有关异甘草素（Isoliquiiritigenin，ISL）是甘草中的一种黄酮类化合物，在动物模型中被报道可以预防氧化偶氮甲烷（AOM）诱导的结肠癌的发生。在这里，在结肠炎相关的肿瘤发生的小鼠模型诱导的AOM/葡聚糖硫酸钠（DSS），我们研究了ISL的化学预防作用及其作用机制。用AOM/DSS处理小鼠，并随机接受媒介物或ISL（3、15和75 mg/kg）。肿瘤负荷，组织学，免疫组化，基因和蛋白表达进行了测定。ISL灌胃给药12周，结肠癌的发病率、多样性和肿瘤大小分别显著降低60%、55.4%和42.6%。此外，ISL抑制M2巨噬细胞极化。这种变化伴随着PGE 2和IL-6信号传导的下调。重要的是，氯膦酸盐（Clod）或唑来膦酸（ZA）对巨噬细胞的消耗逆转了ISL的作用。同时，体外研究也证明ISL限制了RAW264.7细胞和小鼠腹腔巨噬细胞的M2极化，同时使PGE2/PPAR δ和IL-6/STAT3信号转导失活。相反，外源性加入PGE2或IL-6，或过表达组成型活性STAT3逆转ISL介导的M2巨噬细胞极化抑制。总之，膳食类黄酮ISL通过阻碍由PGE2和IL-6之间的相互作用介导的M2巨噬细胞极化，有效地抑制结肠炎相关的肿瘤发生。因此，M2巨噬细胞极化的抑制可能是一个有前途的策略，用于结肠直肠癌的化学预防。
M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE2and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE2/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE2or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE2and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer.