title: Lycopene prevention of oxysterol-induced proinflammatory cytokine cascade in human macrophages: inhibition of NF-κB nuclear binding and increase in PPARγ expression.
abstract: 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.
authors.affiliation: Institute of General Pathology, Catholic University- School of Medicine, 00168 Rome, Italy. p.palozza@rm.unicatt.it
authors.forename: Paola
authors.initials: P
authors.lastname: Palozza
authors.forename: Rossella
authors.initials: R
authors.lastname: Simone
authors.forename: Assunta
authors.initials: A
authors.lastname: Catalano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monego
authors.forename: Angela
authors.initials: A
authors.lastname: Barini
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mele
authors.forename: Nadia
authors.initials: N
authors.lastname: Parrone
authors.forename: Sonia
authors.initials: S
authors.lastname: Trombino
authors.forename: Nevio
authors.initials: N
authors.lastname: Picci
authors.forename: Franco O
authors.initials: FO
authors.lastname: Ranelletti
mesh_terms: D002338:Carotenoids / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D006888:Hydroxycholesterols / Q000009:adverse effects*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007653:Ketocholesterols / Q000009:adverse effects*; D000077276:Lycopene; D008264:Macrophages / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000032:analysis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D016207:Cytokines; D006888:Hydroxycholesterols; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D007653:Ketocholesterols; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D002338:Carotenoids; C007997:25-hydroxycholesterol; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; C003001:7-ketocholesterol; D000077276:Lycopene