The chemokine CXCL9 exacerbates chemotherapy-induced acute intestinal damage through inhibition of mucosal restitution
The chemokine CXCL9 exacerbates chemotherapy-induced acute intestinal damage through inhibition of mucosal restitution
复制标题
DOI：
10.1007/s00432-014-1869-y
复制
发表时间：
2015-06
影响因子：
3.6
通讯作者：
Huili Lu;Hongyu Liu;Jiaxian Wang;Jiaqing Shen;Shunyan Weng;Lei Han;T. Sun;Lan Qian;Mingyuan Wu-Mi
中科院分区：
文献类型：
--
作者：
Huili Lu;Hongyu Liu;Jiaxian Wang;Jiaqing Shen;Shunyan Weng;Lei Han;T. Sun;Lan Qian;Mingyuan Wu-Mi
目的化疗药物引起的急性肠损伤往往是临床肿瘤治疗中的剂量限制因素。本研究旨在探讨趋化因子CXCL9对化疗后肠道损伤的影响，并探讨抗CXCL9药物的治疗潜力。方法采用非致瘤性人上皮细胞系MCF10A进行体外细胞增殖试验。通过多途径分析探索CXCL9作用的介导途径，并通过酶联免疫吸附法鉴定相应的下游效应物。采用单次注射化疗药物5-氟尿嘧啶（5-FU）制备化疗致小肠黏膜炎小鼠模型。采用实时荧光定量PCR检测化疗后肠黏膜cxcl9及其受体cxcr3的体内表达情况。研究了抗CXCL9抗体的治疗性治疗，以证实CXCL9可能参与化疗引起的肠上皮损伤的假设。结果scxcl9通过激活p70核糖体S6激酶（p70S6K）磷酸化抑制MCF10A细胞的增殖，进而促进下游效应物转化生长因子β (TGF-β)的分泌。用抑制剂阻断phospho-p70S6K可消除CXCL9对MCF10A细胞的作用，降低TGF-β的分泌。5-FU注射后肠黏膜中cxcl9和cxcr3的表达水平显著上调。用抗cxcr9抗体中和升高的CXCL9成功地增强了肠黏膜的重建，提高了接受大剂量化疗的小鼠的存活率。结论scxcl9通过磷酸化p70S6K抑制上皮细胞增殖，导致TGF-β作为下游介质分泌。CXCL9/CXCR3相互作用可加重化疗药物诱导的肠道损伤，抗CXCL9药物是促进粘膜恢复的潜在新型治疗候选药物。
PurposeAcute intestinal damage induced by chemotherapeutic agent is often a dose-limiting factor in clinical cancer therapy. The aim of this study was to investigate the effect of chemokine CXCL9 on the intestinal damage after chemotherapy and explore the therapeutic potential of anti-CXCL9 agents.MethodsIn vitro cell proliferation assay was performed with a non-tumorigenic human epithelial cell line MCF10A. Multiple pathway analysis was carried out to explore the pathway that mediated the effect of CXCL9, and the corresponding downstream effector was identified with enzyme-linked immunosorbent assays. Chemotherapy-induced mouse model of intestinal mucositis was prepared by a single injection of the chemotherapeutic agent 5-fluorouracil (5-FU). In vivo expression ofcxcl9and its receptorcxcr3in intestinal mucosa after chemotherapy was determined by quantitative real-time PCR. Therapeutic treatment with anti-CXCL9 antibodies was investigated to confirm the hypothesis that CXCL9 can contribute to the intestinal epithelium damage induced by chemotherapy.ResultsCXCL9 inhibited the proliferation of MCF10A cells by activating phosphorylation of p70 ribosomal S6 kinase (p70S6K), which further promotes the secretion of transforming growth factor beta (TGF-β) as the downstream effector. A blockade of phospho-p70S6K with inhibitor abolished the effect of CXCL9 on MCF10A cells and reduced the secretion of TGF-β. The expression levels ofcxcl9andcxcr3were significantly up-regulated in intestinal mucosa after 5-FU injection. Neutralizing elevated CXCL9 with anti-CXCR9 antibodies successfully enhanced reconstitution of intestinal mucosa and improved the survival rate of mice that received high-dose chemotherapy.ConclusionsCXCL9 inhibits the proliferation of epithelial cells via phosphorylation of p70S6K, resulting in the excretion of TGF-β as downstream mediator. CXCL9/CXCR3 interaction can exacerbate chemotherapeutic agent-induced intestinal damage, and anti-CXCL9 agents are potential novel therapeutic candidates for promoting mucosal restitution.