IL-17 producing mast cells promote the expansion of myeloid-derived suppressor cells in a mouse allergy model of colorectal cancer.
IL-17 producing mast cells promote the expansion of myeloid-derived suppressor cells in a mouse allergy model of colorectal cancer.
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DOI：
10.18632/oncotarget.5435
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发表时间：
2015-10-20
期刊：
影响因子：
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通讯作者：
Wang TC
中科院分区：
文献类型：
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作者：
Chen X;Churchill MJ;Nagar KK;Tailor YH;Chu T;Rush BS;Jiang Z;Wang EB;Renz BW;Wang H;Fung MC;Worthley DL;Mukherjee S;Wang TC
食物过敏可以影响结直肠癌的发展，尽管潜在的机制尚不清楚。肥大细胞(MC)储存和分泌组胺，而未成熟的髓样细胞(IMC)是组氨酸脱羧酶(HDC)表达的主要部位，HDC是负责组胺产生的酶。根据我们早期的工作，我们假设组胺通过影响MC-MDSC轴而在过敏和结直肠癌发生之间的联系中发挥中心作用。在这里，我们表明，在野生型(WT)小鼠，卵清蛋白(OVA)免疫引起典型的TH2反应。相反，在HDC−/−小鼠中，对卵清蛋白过敏的反应偏向于表达IL-17的MC的渗透。这种反应被组胺治疗所抑制。表达IL-17的DC刺激−/−增殖，上调COX-2和Arg-1的表达。在−/−肿瘤细胞移植模型和AOM/DSS致癌模型中，hdc-dc38小鼠的卵子过敏增加了结肠癌细胞的生长。综上所述，我们的结果表明，组胺抑制了IL-17表达的MC及其随后对MDSCs的激活，从而降低了食物过敏背景下结直肠癌的风险。靶向MC-MDSC轴可能对癌症患者的预防和治疗有用，特别是对那些有食物过敏的患者。
Food allergy can influence the development of colorectal cancer, although the underlying mechanisms are unclear. While mast cells (MC) store and secrete histamine, immature myeloid cells (IMC) are the major site of histidine decarboxylase (HDC) expression, the enzyme responsible for histamine production. From our earlier work, we hypothesized that histamine is central to the association between allergy and colorectal carcinogenesis through its influence on the MC-MDSC axis. Here, we show that in wild type (WT) mice, ovalbumin (OVA) immunization elicits a typical TH2 response. In contrast, in HDC−/− mice, the response to OVA allergy is skewed towards infiltration by IL-17 expressing MCs. This response is inhibited by histamine treatment. The HDC−/− allergic IL-17-expressing MCs promote MDSC proliferation and upregulation of Cox-2 and Arg-1. OVA allergy in HDC−/− mice increases the growth of colon tumor cells in both the MC38 tumor cell implantation model and the AOM/DSS carcinogenesis model. Taken together, our results show that histamine represses IL-17-expressing MCs and their subsequent activation of MDSCs, attenuating the risk of colorectal cancer in the setting of food allergy. Targeting the MC-MDSC axis may be useful for cancer prevention and treatment in patients, particularly in those with food allergy.