Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil
Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil
复制标题
CXCL4/CXCR3 轴激活 p38-MAPK 有助于 5-氟尿嘧啶引发的 p53 依赖性肠细胞凋亡
DOI：
10.4161/cbt.29114
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发表时间：
2014-08-01
影响因子：
3.6
通讯作者：
Han, Wei
中科院分区：
文献类型：
--
作者：
Gao, Jing;Gao, Jin;Han, Wei
化疗引起的粘膜炎 (CIM) 是 5-氟尿嘧啶 (5-FU) 等化疗药物的主要副作用。参与这种疾病过程的分子仍未完全了解。我们提出 CIM 期间的稳态调节基因可能参与了该疾病。先前通过 5-FU 诱导的粘膜炎模型中小鼠空肠的表达基因阵列鉴定了一组此类基因。在这里，我们报道CXCL4就是这样一个稳态调节基因，并作为CIM抗体治疗的新靶点。 CXCL4 及其受体 CXCR3 在基因和蛋白质水平上均被证实在 5-FU 诱导的粘膜炎期间受到稳态调节。在 5-FU 小鼠 CIM 模型中，使用 CXCL4 中和单克隆抗体 (CXCL4mab) 可降低化疗引起的腹泻（CIM 的主要症状）的发生率、严重程度和持续时间。从机制上讲，CXCL4mab 通过其受体 CXCR3 抑制 5-FU 诱导的 p53 和 Bax 表达，从而减少隐窝上皮细胞的凋亡。在肠上皮细胞系 (IEC-6) 中鉴定了 CXCL4 激活上皮细胞凋亡的下游信号通路。 CXCL4 激活 p38 MAPK 的磷酸化，从而介导 p53 和 Bax 的刺激表达，并导致 Caspase-8、-9 和 -3 的最终激活。总之，小鼠中 5-FU 激活 CXCL4 表达，通过激活 p38-MAPK 上调 p53，参与 5-FU 诱导的肠粘膜炎，并且 CXCL4mab 可能有益于预防肠道中的 CIM。
Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.