Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs: synergistic effects of doxorubicin and vincristine.
Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs: synergistic effects of doxorubicin and vincristine.
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DOI：
10.4161/cbt.29922
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发表时间：
2014-10
影响因子：
3.6
通讯作者：
Wood LJ
中科院分区：
文献类型：
--
作者：
Wong J;Tran LT;Magun EA;Magun BE;Wood LJ
细胞毒性化疗药物，特别是联合使用时，被广泛用于治疗患者的各种癌症，但通常会导致严重症状，对身体功能和生活质量产生负面影响。有令人信服的证据表明，这些症状的病因涉及细胞毒性化疗诱导的炎症。由于IL-1β在免疫应答中作为起始细胞因子起着核心作用，我们比较了已知诱导IL-1β产生的药物阿霉素与其他10种常用化疗药物导致原代小鼠巨噬细胞加工和分泌IL-1β的能力。其中7种药物（美法仑、顺铂、长春新碱、依托泊苷、紫杉醇、甲氨蝶呤和阿糖胞苷）可引起脂多糖预处理细胞产生IL-1β。当与多柔比星联合给药时，其中一种药物长春新碱也能够协同激活NLRP 3依赖性炎性小体并增加IL-1β、IL-6和CXCL 1的表达。TNF-α和IL-1信号的缺乏导致成熟IL-1β的产生部分减少。当多柔比星和长春新碱单独或联合使用时，已知抑制丝裂原活化激酶（MAPK）上游激酶活性的三种小分子抑制剂可抑制IL-1β、IL-6和CXCL 1的表达，因此特异性激酶抑制剂可用于减轻接受化疗患者的炎症。
Cytotoxic chemotherapeutic drugs, especially when used in combination, are widely employed to treat a variety of cancers in patients but often lead to serious symptoms that negatively affect physical functioning and quality of life. There is compelling evidence that implicates cytotoxic chemotherapy-induced inflammation in the etiology of these symptoms. Because IL-1β plays a central role as an initiator cytokine in immune responses, we compared doxorubicin, a drug known to induce IL-1β production, with ten other commonly prescribed chemotherapeutic drugs in their ability to lead to processing and secretion of IL-1β by primary mouse macrophages. Seven of them (melphalan, cisplatin, vincristine, etoposide, paclitaxel, methotrexate, and cytarabine) caused the production of IL-1β in cells pretreated with lipopolysaccharide. When delivered in combination with doxorubicin, one of the drugs, vincristine, was also capable of synergistically activating the NLRP3-dependent inflammasome and increasing expression of IL-1β, IL-6, and CXCL1. The absence of TNF-α and IL-1 signaling caused a partial reduction in the production of mature IL-1β. Three small-molecule inhibitors known to suppress activity of kinases situated upstream of mitogen-activated kinases (MAPKs) inhibited the expression of IL-1β, IL-6, and CXCL1 when doxorubicin and vincristine were used singly or together, so specific kinase inhibitors may be useful in reducing inflammation in patients receiving chemotherapy.
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影响因子：
2.2
作者：
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通讯作者：
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50.3
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通讯作者：
Clackson, Tim