Institute of General Pathology, Catholic University, Rome, Italy.
PLoS One. 2011;6(5):e19652. doi: 10.1371/journal.pone.0019652. Epub 2011 May 19.
Increasing evidence suggests that lycopene, the major carotenoid present in tomato, may be preventive against smoke-induced cell damage. However, the mechanisms of such a prevention are still unclear. The aim of this study was to investigate the role of lycopene on the production of the pro-inflammatory cytokine IL-8 induced by cigarette smoke and the possible mechanisms implicated. Therefore, human THP-1 macrophages were exposed to cigarette smoke extract (CSE), alone and following a 6-h pre-treatment with lycopene (0.5-2 µM). CSE enhanced IL-8 production in a time- and a dose-dependent manner. Lycopene pre-treatment resulted in a significant inhibition of CSE-induced IL-8 expression at both mRNA and protein levels. NF-kB controlled the transcription of IL-8 induced by CSE, since PDTC prevented such a production. Lycopene suppressed CSE-induced NF-kB DNA binding, NF-kB/p65 nuclear translocation and phosphorylation of IKKα and IkBα. Such an inhibition was accompanied by a decrease in CSE-induced ROS production and NOX-4 expression. Lycopene further inhibited CSE-induced phosphorylation of the redox-sensitive ERK1/2, JNK and p38 MAPKs. Moreover, the carotenoid increased PPARγ levels which, in turn, enhanced PTEN expression and decreased pAKT levels in CSE-exposed cells. Such effects were abolished by the PPARγ inhibitor GW9662. Taken together, our data indicate that lycopene prevented CSE-induced IL-8 production through a mechanism involving an inactivation of NF-kB. NF-kB inactivation was accompanied by an inhibition of redox signalling and an activation of PPARγ signalling. The ability of lycopene in inhibiting IL-8 production, NF-kB/p65 nuclear translocation, and redox signalling and in increasing PPARγ expression was also found in isolated rat alveolar macrophages exposed to CSE. These findings provide novel data on new molecular mechanisms by which lycopene regulates cigarette smoke-driven inflammation in human macrophages.
越来越多的证据表明，番茄中主要的类胡萝卜素番茄红素可能具有预防烟雾引起的细胞损伤的作用。然而，这种预防的机制尚不清楚。本研究旨在探讨番茄红素对香烟烟雾诱导的促炎细胞因子 IL-8 产生的作用及其可能涉及的机制。因此，人 THP-1 巨噬细胞分别或用番茄红素（0.5-2μM）预处理 6 小时后暴露于香烟烟雾提取物（CSE）中。CSE 以时间和剂量依赖的方式增强了 IL-8 的产生。番茄红素预处理可显著抑制 CSE 诱导的 IL-8 表达在 mRNA 和蛋白质水平。NF-κB 控制 CSE 诱导的 IL-8 转录，因为 PDTC 可预防这种产生。番茄红素抑制 CSE 诱导的 NF-κB DNA 结合、NF-κB/p65 核易位和 IKKα和 IkBα磷酸化。这种抑制伴随着 CSE 诱导的 ROS 产生和 NOX-4 表达的减少。番茄红素进一步抑制 CSE 诱导的氧化还原敏感的 ERK1/2、JNK 和 p38 MAPKs 的磷酸化。此外，类胡萝卜素增加了 PPARγ 水平，进而增加了 CSE 暴露细胞中 PTEN 的表达并降低了 pAKT 水平。这种作用被 PPARγ 抑制剂 GW9662 所消除。总之，我们的数据表明，番茄红素通过一种涉及 NF-κB 失活的机制来防止 CSE 诱导的 IL-8 产生。NF-κB 失活伴随着氧化还原信号的抑制和 PPARγ 信号的激活。在暴露于 CSE 的分离的大鼠肺泡巨噬细胞中，也发现了番茄红素抑制 IL-8 产生、NF-κB/p65 核易位、氧化还原信号和增加 PPARγ 表达的能力。这些发现为番茄红素调节人巨噬细胞中香烟烟雾驱动的炎症的新分子机制提供了新的数据。
