Lycopene prevention of oxysterol-induced pro-inflammatory cytokine cascade in human macrophages: inhibition of NF-kB nuclear binding and increase in PPARgamma; expression

It is now well accepted that oxysterols play important roles in the formation of atherosclerotic plaque, involving cytotoxic, pro-oxidant and pro-inflammatory processes. It has been recently suggested that tomato lycopene may act as a preventive agent in atherosclerosis, although the exact mechanism of such a protection is not clarified. The main aim of this study was to investigate whether lycopene is able to counteract oxysterol-induced pro-inflammatory cytokines cascade in human macrophages, limiting the formation of atherosclerotic plaque. Therefore, THP-1 macrophages were exposed to two different oxysterols, such as 7-keto-cholesterol (7-KC) (4-16 μM) and 25- hydroxycholesterol (25-OHC) (2-4 μM), alone and in combination with lycopene (0.5-2 μM). Both oxysterols enhanced pro-inflammatory cytokine (IL-1β, IL-6, IL-8, TNFα) secretion and mRNA levels in a dose-dependent manner, although at different extent. These effects were associated with an increased reactive oxygen species (ROS) production through an enhanced expression of NAD(P)H oxidase (NOX-4). Moreover, a net increment of phosphorylation of ERK1/2, p-38 and JNK and of nuclear factor kB (NF-kB) nuclear binding was observed. Lycopene prevented oxysterol-induced increase in pro-inflammatory citokine secretion and expression. Such an effect was accompanied by an inhibition of oxysterol-induced ROS production, MAPK phosphorylation and NF-kB activation. Moreover, the carotenoid increased PPARγ levels in THP-1 macrophages. Taken all together, these data bring new information on the anti-atherogenic properties of lycopene, and on its mechanisms of action in atherosclerosis prevention.