Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response.
Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response.
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肥胖通过促进未成熟髓系细胞迁移和辅助性T细胞17（TH17）应答，加速了幽门螺杆菌诱导的胃癌发生。
DOI：
10.1136/gutjnl-2013-305092
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发表时间：
2014-03
期刊：
影响因子：
24.5
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
Ericksen RE;Rose S;Westphalen CB;Shibata W;Muthupalani S;Tailor Y;Friedman RA;Han W;Fox JG;Ferrante AW Jr;Wang TC
探讨幽门螺杆菌诱导的慢性胃炎症中肥胖相关炎症和免疫调节在胃癌发生中的作用。C57BL/6雄性小鼠感染了狐猴，并被置于高脂肪饮食中（45%的热量来自脂肪）。分析研究动物的胃和脂肪病理，血清、胃和脂肪组织的炎症标志物，以及血液、脾、胃和脂肪组织的免疫反应。与瘦的对照组相比，饮食诱导的肥胖小鼠中H felis诱导的胃癌发生加速。肥胖增加了H felis感染小鼠血液和胃组织中骨髓来源的未成熟骨髓细胞。肥胖还导致H felis感染小鼠胃组织中CD4 T细胞、IL-17A、粒细胞巨噬细胞集落刺激因子、磷酸化STAT3和促生存基因表达升高。相反，在肥胖小鼠的脂肪组织中，H felis感染增加了巨噬细胞的积累和IL-6、C-C基序配体7 （CCL7）和瘦素的表达。最后，肥胖和胃炎症联合作用可协同提高血清促炎因子，包括IL-6。在这里，我们建立了一个模型来研究肥胖使个体易患胃癌的分子机制。在感染H - felis的小鼠中，肥胖增加了促炎免疫反应，加速了胃癌的发生。有趣的是，在肥胖而非瘦的小鼠中，胃炎症增强了肥胖诱导的脂肪炎症和脂肪衍生因子的产生。我们的研究结果表明，肥胖通过炎症胃和脂肪组织之间的细胞因子介导的串扰加速了幽门螺杆菌相关胃癌的发生，增强了这两个组织部位的免疫反应，从而促进了胃微环境的致癌变。
To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.
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