IL-1Ra selectively protects intestinal crypt epithelial cells, but not tumor cells, from chemotoxicity via p53-mediated upregulation of p21WAF1 and p27KIP1
IL-1Ra selectively protects intestinal crypt epithelial cells, but not tumor cells, from chemotoxicity via p53-mediated upregulation of p21WAF1 and p27KIP1
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IL-1Ra 通过 p53 介导的 p21(WAF1) 和 p27(KIP1) 上调选择性保护肠隐窝上皮细胞（而非肿瘤细胞）免受化学毒性
DOI：
10.1016/j.phrs.2014.03.007
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发表时间：
2014-04-01
影响因子：
9.3
通讯作者：
Han, Wei
中科院分区：
文献类型：
--
作者：
Wang, Xia;Zhu, Shunying;Han, Wei
化疗诱导的肠粘膜炎（CIM）是一种主要的剂量限制性副作用，由化疗药物（包括5-氟尿嘧啶（5-FU）和伊立替康（CPT-11））的非特异性细胞清除作用引起。迫切需要为可预测的CIM制定预防战略。以前，我们已经证明了重组人白细胞介素-1受体拮抗剂（rhIL-1 Ra）在预防环磷酰胺诱导的小鼠粘膜炎中的重要作用。在这项研究中，rhIL-1 Ra的预防作用进一步评估在5-FU和CPT-11诱导的粘膜炎小鼠模型。rhIL-1 Ra预处理通过减少野生型小鼠的隐窝凋亡和改善隐窝存活来降低化疗诱导的腹泻的发生率、严重程度和持续时间，但在IL-1 RI（-1-）、p53（-/-）和p21（-/-）小鼠中没有。进一步的研究表明，rhIL-1 Ra通过提高p21（WAF 1）和p27（KIP 1）的表达水平，促进肠隐窝上皮细胞（ICE）的细胞周期阻滞，而IL-1 RI（-/-）和p53（-/-）小鼠以及p21（WAF 1）和p27（KIP 1）沉默的IEC-6细胞的细胞周期阻滞被消除。重要的是，在肿瘤细胞系培养物和同基因肿瘤移植小鼠模型中，肿瘤生长和对化疗的敏感性不受rhIL-1 Ra的影响。目前的研究表明，rhIL-1 Ra有效地和特异性地保护ICE免受化学毒性，通过可逆地降低IL-1信号的基础水平，以促进正常细胞周期阻滞，但不是肿瘤细胞。我们的研究结果支持rhIL-1 Ra预防CIM的临床开发。(C)2014爱思唯尔有限公司版权所有。
Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect, resulting from the nonspecific cytoablative actions of chemoagents, including 5-fluorouracil (5-FU) and irinotecan (CPT-11). Preventive strategies are urgently needed for the predictable CIM. Previously, we have demonstrated an important role of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) in the prevention of cyclophosphamide-induced mucositis in mice. In this study, the preventive role of rhIL-1Ra was further evaluated in 5-FU- and CPT-11-induced mucositis mouse models. rhIL-1Ra pretreatment reduced the incidence, severity, and duration of chemotherapy-induced diarrhea, through attenuating crypt apoptosis and improving crypt survival in wild-type mice, but not in IL-1RI(-1-), p53(-/-), and p21(-/-) mice. Further studies demonstrated that rhIL-1Ra promoted the cell cycle arrest of intestinal crypt epithelia (ICE) through elevating the cellular level of p21(WAF1) and p27(KIP1), which was abolished in IL-1RI(-/-) and p53(-/-) mice, and in p21(WAF1) and p27(KIP1) silenced IEC-6 cells. Importantly, the tumor growth and sensitivity to chemotherapy were not affected by rhIL-1Ra in cultures of tumor cell lines and in a syngeneic tumor-transplantation mouse model. The present study demonstrated that rhIL-1Ra effectively and specifically protected ICE from chemotoxicity through reversible reduction of the basal level of IL-1 signaling to promote normal cell cycle arrest, but not tumor cells. Our findings support the clinical development of rhIL-1Ra in the prevention of CIM. (C) 2014 Elsevier Ltd. All rights reserved.