Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines
Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines
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DOI：
10.1093/carcin/bgi061
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发表时间：
2005-07-01
期刊：
影响因子：
4.7
通讯作者：
Malkinson, AM
中科院分区：
文献类型：
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作者：
Dwyer-Nield, LD;Srebernak, MC;Malkinson, AM
使用转基因和基因敲除小鼠的研究表明，特定的细胞因子影响肺癌的生长，并确定前列腺素E-2(PGE(2))、前列环素(PGI(2))和一氧化氮(NO)是这一过程的关键介质。PGE(2)和NO具有促肿瘤作用，而PGI(2)具有抗肿瘤作用。在此，我们描述了一种体外实验方法来研究细胞因子、前列腺素(PGs)和一氧化氮之间的相互作用。检测非致瘤小鼠肺上皮细胞系、其自发转化体和小鼠肺肿瘤来源细胞系单独或联合作用于细胞因子肿瘤坏死因子α、干扰素γ和白介素1β前后培养上清液中PGE(2)、PGI(2)和NO水平。肿瘤细胞产生的PGE(2)多于PGI(2)，而非肿瘤细胞的PGE(2)高于PGI(2)。细胞因子的暴露放大了这些不同浓度的程度。在化学诱导的小鼠肺肿瘤中，前列腺素E(2)/前列环素(2)的比率也高于邻近组织或对照肺，支持这一体外模型的生理学相关性。PG生物合成酶在这些细胞系中的表达与相应PG的产生有关。细胞因子治疗通过诱导炎症相关的生物合成酶-诱导型一氧化氮合酶(INOS)来增加NO的产生，但这与细胞的肿瘤状态无关。用氨基胍或NS-398分别抑制iNOS和环氧合酶2的活性，表明NO不影响PG的产生，PGs也不影响NO的产生。由于缺乏iNOS抑制小鼠肺肿瘤的形成，我们认为这不依赖于上皮细胞PG合成的任何调节。PGE(2)/PGI(2)比率在体外和体内的相似正常/肿瘤趋势，加上细胞因子暴露时这种差异的放大，与炎症期间释放的细胞因子加剧肿瘤和正常肺细胞行为差异的假设是一致的。
Studies using transgenic and knockout mice have demonstrated that particular cytokines influence lung tumor growth and identified prostaglandin E-2 (PGE(2)), prostacyclin (PGI(2)) and nitric oxide (NO) as critical mediators of this process. PGE(2) and NO were pro-tumorigenic while PGI(2) was antitumorigenic. We describe herein an in vitro experimental approach to examine interactions among cytokines, prostaglandins (PGs) and NO. PGE(2), PGI(2), and NO levels were assayed in culture media from non-tumorigenic mouse lung epithelial cell lines, their spontaneous transformants and mouse lung tumor-derived cell lines, before or after exposure to the cytokines TNF alpha, IFN gamma and IL1 beta, alone and in combination. More PGE(2) than PGI(2) was produced by neoplastic cells, while the opposite was observed in non-tumorigenic lines. Cytokine exposure magnified the extent of these differential concentrations. The PGE(2) to PGI(2) ratio was also greater in chemically-induced mouse lung tumors than in adjacent tissue or control lungs, supporting the physiological relevance of this in vitro model. Expression of PG biosynthetic enzymes in these cell lines correlated with production of the corresponding PGs. Cytokine treatment enhanced NO production by inducing the inflammation-associated biosynthetic enzyme, inducible NO synthase (iNOS), but this did not correlate with the neoplastic status of cells. Inhibition of iNOS or cyclooxygenase 2 activity using aminoguanidine or NS-398 respectively, demonstrated that NO did not affect PG production nor did PGs influence NO production. Since lack of iNOS inhibits mouse lung tumor formation, we propose that this is independent of any modulation of PG synthesis in epithelial cells. The similar normal/neoplastic trends in PGE(2) to PGI(2) ratios both in vitro and in vivo, together with an amplification of this difference upon cytokine exposure, are consistent with the hypothesis that cytokines released during inflammation exacerbate differences in the behavior of neoplastic and normal lung cells.