Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line
Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line
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DOI：
10.4049/jimmunol.172.10.6330
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发表时间：
2004-05-15
影响因子：
4.4
通讯作者：
Travers, JB
中科院分区：
文献类型：
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作者：
Darst, M;Al-Hassani, M;Travers, JB
除了已知的细胞毒作用外，化疗药物还可以在肿瘤细胞中激发细胞因子的产生。此外，许多化疗药物是强有力的促氧化应激源。尽管脂质介质血小板激活因子(PAF)是在氧化应激下合成的，许多表皮癌表达与细胞因子产生相关的PAF受体(PAF-R)，但PAF是否参与化疗药物诱导的细胞因子产生尚不清楚。这些研究利用逆转录病毒转导PAF-R阴性的人表皮癌细胞系KB和人PAF-R建立了一个模型系统，研究了PAF-R系统在化疗介导的细胞因子产生中的作用。在KB细胞中，PAF-R的存在导致化疗药物依托泊苷和丝裂霉素C诱导的细胞因子IL-8和TNF-α的产生增加，这种作用是PAF-R所特有的，因为fMLP的G蛋白偶联受体的表达不影响化疗药物诱导的细胞因子的产生。此外，使用可诱导的反义PAF-R策略消融上皮细胞系HaCaT中的天然PAF-R可抑制依托泊苷诱导的细胞因子的产生。氧化应激和转录因子NF-kappaB被发现参与了这种增强效应，因为它是由氧化剂叔丁基氢过氧化氢模拟的，而叔丁基氢过氧化氢既可以被抗氧化剂阻断，也可以通过使用超级阻滞剂IkappaBM突变体抑制NFkappaB途径。这些研究为一种新的途径提供了证据，通过该途径，表皮PAF-R可以通过依赖于NF-kappaB的过程来增加化疗诱导的细胞因子的产生。
addition to their known cytotoxic effects, chemotherapeutic agents can trigger cytokine production in tumor cells. Moreover, many chemotherapeutic agents are potent pro-oxidative stressors. Although the lipid mediator platelet-activating factor (PAF) is synthesized in response to oxidative stress, and many epidermal carcinomas express PAF receptors (PAF-R) linked to cytokine production, it is not known whether PAF is involved in chemotherapeutic agent-induced cytokine production. These studies examined the role of the PAF system in chemotherapy-mediated cytokine production using a model system created by retroviral-mediated transduction of the PAF-R-negative human epidermal carcinoma cell line KB with the human PAF-R. The presence of the PAF-R in KB cells resulted in augmentation of the production of cytokines IL-8 and TNF-alpha induced by the chemotherapeutic agents etoposide and mitomycin C. These effects were specific for the PAF-R, as expression of the G protein-coupled receptor for fMLP did not affect chemotherapeutic agent-induced cytokine production. Moreover, ablation of the native PAF-R in the epithelial cell line HaCaT using an inducible antisense PAF-R strategy inhibited etoposide-induced cytokine production. Oxidative stress and the transcription factor NF-kappaB were found to be involved in this augmentative effect, because it was mimicked by the oxidant tert-butyl-hydroperoxide, which was blocked both by antioxidants and by inhibition of the NFkappaB pathway using a super-repressor IkappaBM mutant. These studies provide evidence for a novel pathway by which the epidermal PAF-R can augment chemotherapy-induced cytokine production through an NF-kappaB-dependent process.