Palozza Paola, Simone Rossella E, Catalano Assunta, Saraceni Flavia, Celleno Leonardo, Mele Maria Cristina, Monego Giovanni, Cittadini Achille
Institute of General Pathology, Catholic University School of Medicine, L. Go F. Vito, 100168 Rome, Italy.
Inflamm Allergy Drug Targets. 2012 Feb;11(1):36-47. doi: 10.2174/187152812798889376.
Matrix metalloproteinase-9 (MMP-9) has been implicated in both inflammation and fibrosis. It has been reported that cigarette smoke induced MMP-9 expression and that lycopene may act as an anti-inflammatory agent and may counteract several signal pathways affected by cigarette smoke exposure. However, at the moment, it is unknown if lycopene may inhibit cigarette smoke-induced MMP-9 expression. Presently, we examined the inhibitory mechanism of lycopene on MMP-9 induction in cultured human macrophages (THP-1 cells), in isolated rat alveolar macrophages (AMs) and in cultured RAT-1 fibroblasts, all cellular sources of MMP-9, exposed to cigarette smoke extract (CSE). CSE induced a marked increase in MMP-9 expression in cultured as well as in isolated cells. A 8 h-lycopene pre-treatment (0.5-2 μM) reduced CSE-mediated MMP-9 induction in a dose- and time-dependent manner. Lycopene attenuated CSE-mediated activation of Ras, enhancing the levels of this protein in the cytosolic fraction. Moreover, lycopene inhibited CSE-induced ERK1/2 and NF-κB activation in a dose-dependent manner. Lycopene-mediated inhibition of MMP-9 was reversed by mevalonate and associated with a reduced expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Taken together, these results suggest that lycopene may inhibit CSE-mediated MMP-9 induction, primarily by blocking prenylation of Ras in a signaling pathway, in which MEK1/2-ERK1/2 and NF-κB are involved.
基质金属蛋白酶-9（MMP-9）与炎症和纤维化均有关联。据报道，香烟烟雾可诱导MMP-9表达，而番茄红素可能作为一种抗炎剂，抵消香烟烟雾暴露所影响的多种信号通路。然而，目前尚不清楚番茄红素是否能抑制香烟烟雾诱导的MMP-9表达。目前，我们研究了番茄红素对培养的人巨噬细胞（THP-1细胞）、分离的大鼠肺泡巨噬细胞（AMs）以及培养的RAT-1成纤维细胞（这些都是MMP-9的细胞来源）中MMP-9诱导的抑制机制，这些细胞均暴露于香烟烟雾提取物（CSE）中。CSE可诱导培养细胞和分离细胞中MMP-9表达显著增加。8小时的番茄红素预处理（0.5 - 2μM）以剂量和时间依赖的方式降低了CSE介导的MMP-9诱导。番茄红素减弱了CSE介导的Ras激活，提高了该蛋白在胞质部分的水平。此外，番茄红素以剂量依赖的方式抑制CSE诱导的ERK1/2和NF-κB激活。番茄红素介导的MMP-9抑制作用被甲羟戊酸逆转，并与3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶表达降低有关。综上所述，这些结果表明番茄红素可能主要通过在MEK1/2 - ERK1/2和NF-κB参与的信号通路中阻断Ras的异戊二烯化来抑制CSE介导的MMP-9诱导。
