Lycopene inhibits NF-kB-mediated IL-8 expression and changes redox and PPARγ signalling in cigarette smoke-stimulated macrophages

Increasing evidence suggests that lycopene, the major carotenoid present in tomato, may be\r\npreventive against smoke-induced cell damage. However, the mechanisms of such a prevention are still\r\nunclear. The aim of this study was to investigate the role of lycopene on the production of the proinflammatory\r\ncytokine IL-8 induced by cigarette smoke and the possible mechanisms implicated.\r\nTherefore, human THP-1 macrophages were exposed to cigarette smoke extract (CSE), alone and\r\nfollowing a 6-h pre-treatment with lycopene (0.5-2 μM). CSE enhanced IL-8 production in a time- and a\r\ndose-dependent manner. Lycopene pre-treatment resulted in a significant inhibition of CSE-induced\r\nIL-8 expression at both mRNA and protein levels. NF-kB controlled the transcription of IL-8 induced by\r\nCSE, since PDTC prevented such a production. Lycopene suppressed CSE-induced NF-kB DNA binding,\r\nNF-kB/p65 nuclear translocation and phosphorylation of IKKa and IkBa. Such an inhibition was\r\naccompanied by a decrease in CSE-induced ROS production and NOX-4 expression. Lycopene further\r\ninhibited CSE-induced phosphorylation of the redox-sensitive ERK1/2, JNK and p38 MAPKs. Moreover,\r\nthe carotenoid increased PPARg levels which, in turn, enhanced PTEN expression and decreased pAKT\r\nlevels in CSE-exposed cells. Such effects were abolished by the PPARγ inhibitor GW9662. Taken\r\ntogether, our data indicate that lycopene prevented CSE-induced IL-8 production through a mechanism\r\ninvolving an inactivation of NF-kB. NF-kB inactivation was accompanied by an inhibition of redox\r\nsignalling and an activation of PPARγ signalling. The ability of lycopene in inhibiting IL-8 production,\r\nNF-kB/p65 nuclear translocation, and redox signalling and in increasing PPARγ expression was also\r\nfound in isolated rat alveolar macrophages exposed to CSE. These findings provide novel data on new\r\nmolecular mechanisms by which lycopene regulates cigarette smoke-driven inflammation in human\r\nmacrophages.