Lycopene prevention of oxysterol-induced proinflammatory cytokine cascade in human macrophages: inhibition of NF-κB nuclear binding and increase in PPARγ expression

• Published in: The Journal of nutritional biochemistry 2011-03, Vol.22 (3), p.259-268
• Main Authors: Palozza, Paola, Simone, Rossella, Catalano, Assunta, Monego, Giovanni, Barini, Angela, Mele, Maria Cristina, Parrone, Nadia, Trombino, Sonia, Picci, Nevio, Ranelletti, Franco O.
• Format: Article
• Language: English
• Subjects: Arteriosclerosis; Biological and medical sciences; Carotenoids - pharmacology; Cell Line; Cytokines - biosynthesis; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Humans; Hydroxycholesterols - adverse effects; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Interleukin-8 - metabolism; Ketocholesterols - adverse effects; Lycopene; Lycopersicon esculentum; Macrophages - metabolism; Mitogen-Activated Protein Kinases - metabolism; NADPH Oxidases - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB; Oxysterols; Phosphorylation; Plaque, Atherosclerotic - metabolism; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Pro-inflammatory cytokine cascade; Protein Binding; Reactive Oxygen Species - analysis; RNA, Messenger - analysis; ROS; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2010.02.003

It is now well accepted that oxysterols play important roles in the formation of atherosclerotic plaque, involving cytotoxic, pro-oxidant and proinflammatory 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 proinflammatory 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 (4-16 μM) and 25-hydroxycholesterol (2-4 μM), alone and in combination with lycopene (0.5–2 μM). Both oxysterols enhanced pro-inflammatory cytokine [interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor α) 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. Moreover, a net increment of phosphorylation of extracellular regulated kinase 1/2, p-38 and Jun N-terminal kinase and of nuclear factor kB (NF-κB) nuclear binding was observed. Lycopene prevented oxysterol-induced increase in pro-inflammatory cytokine secretion and expression. Such an effect was accompanied by an inhibition of oxysterol-induced ROS production, mitogen-activated protein kinase phosphorylation and NF-κB activation. The inhibition of oxysterol-induced cytokine stimulation was also mimicked by the specific NF-κB inhibitor pyrrolidine dithiocarbamate. Moreover, the carotenoid increased peroxisome proliferator-activated receptor γ 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.