Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines.
Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines.
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DOI：
10.1006/cyto.2001.0935
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发表时间：
2001-08
期刊：
影响因子：
3.8
通讯作者：
Meirav Zaks-Zilberman;T. Zaks;S. Vogel
中科院分区：
文献类型：
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作者：
Meirav Zaks-Zilberman;T. Zaks;S. Vogel
在鼠巨噬细胞中，抗肿瘤剂紫杉醇诱导多种炎症和抗炎基因的表达，并通过与脂多糖（LPS）（革兰氏阴性菌的内毒素组分）参与的信号传导途径重叠的信号传导途径引起细胞因子分泌。使用半定量RT-PCR检测基因表达，再加上ELISA检测分泌的基因产物，我们分析了广泛的面板的细胞因子和非细胞因子基因诱导紫杉醇和LPS在小鼠DA-3乳腺癌细胞系的反应。所检查的基因的子集（例如，在DA-3细胞系中，LPS和紫杉醇均上调>3-20倍，而IP-10 mRNA被紫杉醇诱导，但不被LPS诱导。在人MDA-MB-231乳腺癌细胞系中，LPS还显着增加GM-CSF和IP-10的mRNA水平，而紫杉醇增加IP-10 mRNA水平，但动力学延迟，并且未能诱导GM-CSF mRNA。小鼠乳腺癌细胞和巨噬细胞的共培养物，用IFN-γ加紫杉醇或LPS刺激，导致一氧化氮的释放增加。由于GM-CSF和IP-10都通过对宿主免疫系统的间接作用或通过抑制肿瘤血管生成而参与体内肿瘤排斥，因此我们的数据加强了肿瘤细胞源性炎症介质可能部分地成为紫杉醇在乳腺癌中的抗肿瘤功效的基础的假设。
In murine macrophages, the anti-tumor agent, paclitaxel, induces expression of a wide variety of inflammatory and anti-inflammatory genes, and causes cytokine secretion via signaling pathways that overlap with those engaged by lipopolysaccharide (LPS), the endotoxic component of Gram-negative bacteria. Using semi-quantitative RT-PCR for detection of gene expression, coupled with ELISA for the detection of secreted gene products, we analyzed the responsiveness of an extensive panel of cytokine and non-cytokine genes to induction by paclitaxel and LPS in the murine DA-3 breast cancer line. A subset of the genes examined (e.g., G-CSF, MIP-2, iNOS, and IL-1 beta, and GM-CSF) was upregulated >3-20-fold by both LPS and paclitaxel in the DA-3 cell line, while IP-10 mRNA was induced by paclitaxel, but not by LPS. In the human MDA-MB-231 breast cancer cell line, LPS also increased mRNA levels for both GM-CSF and IP-10 significantly, while, paclitaxel increased IP-10 mRNA levels with delayed kinetics and failed to induce GM-CSF mRNA. Co-cultures of murine breast cancer cells and macrophages, stimulated with IFN-gamma plus either paclitaxel or LPS, resulted in augmented release of nitric oxide. As both GM-CSF and IP-10 have been implicated in tumor rejection in vivo through either indirect actions on the host immune system or by inhibiting tumor angiogenesis, our data strengthen the hypothesis that tumor cell-derived inflammatory mediators may, in part, underlie the anti-tumor efficacy of paclitaxel in breast cancer.