Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.
Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.
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发表时间：
1998-03
期刊：
影响因子：
11.2
通讯作者：
Min Huang;M. Stolina;Sherven P Sharma;J. Mao;Li Zhu;Patrice W. Miller;J. Wollman;H. Herschman;S. Dubinett
中科院分区：
文献类型：
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作者：
Min Huang;M. Stolina;Sherven P Sharma;J. Mao;Li Zhu;Patrice W. Miller;J. Wollman;H. Herschman;S. Dubinett
肿瘤衍生的前列腺素E2（PGE 2）改变细胞因子平衡并抑制宿主免疫。我们假设肺肿瘤细胞产生高水平的PGE 2依赖于肿瘤环氧化酶（考克斯）-2的表达。我们发现，A549非小细胞肺癌（NSCLC）细胞对白细胞介素（IL）-1 β的反应使PGE 2的产生增加了50倍。通过特异性药物或反义寡核苷酸抑制考克斯-2活性或表达，可抑制IL-1 β诱导的A549细胞中PGE 2的产生。相反，特异性的考克斯-1抑制作用无效。与这些发现一致，IL-1 β诱导A549细胞中考克斯-2 mRNA表达和蛋白质产生。特异性抑制考克斯-2可消除IL-1 β刺激的A549细胞诱导淋巴细胞和巨噬细胞中IL-10的能力。此外，当在肿瘤上清液中培养全血时，特异性抑制A549考克斯-2逆转肿瘤来源的PGE 2依赖性抑制巨噬细胞IL-12产生。我们的研究结果表明，肺肿瘤来源的PGE 2在促进淋巴细胞和巨噬细胞IL-10诱导，同时抑制巨噬细胞IL-12的产生中起着关键作用。从肺癌切除标本中获得的人NSCLC组织的免疫组织化学显示肿瘤细胞内的考克斯-2的细胞质染色。这是第一次描述非小细胞肺癌细胞的功能性考克斯-2表达，并定义了肿瘤考克斯-2表达和高水平的PGE 2产生介导肺癌微环境中细胞因子平衡的深刻改变的途径。
Tumor-derived prostaglandin E2 (PGE2) modifies cytokine balance and inhibits host immunity. We hypothesized that a high level of PGE2 production by lung tumor cells is dependent on tumor cyclooxygenase (COX)-2 expression. We found that PGE2 production by A549 non-small cell lung cancer (NSCLC) cells was elevated up to 50-fold in response to interleukin (IL)-1beta. Reversal of IL-1beta-induced PGE2 production in A549 cells was achieved by specific pharmacological or antisense oligonucleotide inhibition of COX-2 activity or expression. In contrast, specific COX-1 inhibition was not effective. Consistent with these findings, IL-1beta induced COX-2 mRNA expression and protein production in A549 cells. Specific inhibition of COX-2 abrogated the capacity of IL-1beta-stimulated A549 cells to induce IL-10 in lymphocytes and macrophages. Furthermore, specific inhibition of A549 COX-2 reversed the tumor-derived PGE2-dependent inhibition of macrophage IL-12 production when whole blood was cultured in tumor supernatants. Our results indicate that lung tumor-derived PGE2 plays a pivotal role in promoting lymphocyte and macrophage IL-10 induction while simultaneously inhibiting macrophage IL-12 production. Immunohistochemistry of human NSCLC tissues obtained from lung cancer resection specimens revealed cytoplasmic staining for COX-2 within tumor cells. This is the first description of functional COX-2 expression by NSCLC cells and the definition of a pathway whereby tumor COX-2 expression and a high level of PGE2 production mediate profound alteration in cytokine balance in the lung cancer microenvironment.