Abstract
Increasing evidence suggests that lycopene, the major carotenoid present in tomato, may be preventive against smoke-induced cell damage. However, the mechanisms of such a prevention are still unclear. The aim of this study was to investigate the role of lycopene on the production of the pro-inflammatory cytokine IL-8 induced by cigarette smoke and the possible mechanisms implicated. Therefore, human THP-1 macrophages were exposed to cigarette smoke extract (CSE), alone and following a 6-h pre-treatment with lycopene (0.5–2 µM). CSE enhanced IL-8 production in a time- and a dose-dependent manner. Lycopene pre-treatment resulted in a significant inhibition of CSE-induced IL-8 expression at both mRNA and protein levels. NF-kB controlled the transcription of IL-8 induced by CSE, since PDTC prevented such a production. Lycopene suppressed CSE-induced NF-kB DNA binding, NF-kB/p65 nuclear translocation and phosphorylation of IKKα and IkBα. Such an inhibition was accompanied by a decrease in CSE-induced ROS production and NOX-4 expression. Lycopene further inhibited CSE-induced phosphorylation of the redox-sensitive ERK1/2, JNK and p38 MAPKs. Moreover, the carotenoid increased PPARγ levels which, in turn, enhanced PTEN expression and decreased pAKT levels in CSE-exposed cells. Such effects were abolished by the PPARγ inhibitor GW9662. Taken together, our data indicate that lycopene prevented CSE-induced IL-8 production through a mechanism involving an inactivation of NF-kB. NF-kB inactivation was accompanied by an inhibition of redox signalling and an activation of PPARγ signalling. The ability of lycopene in inhibiting IL-8 production, NF-kB/p65 nuclear translocation, and redox signalling and in increasing PPARγ expression was also found in isolated rat alveolar macrophages exposed to CSE. These findings provide novel data on new molecular mechanisms by which lycopene regulates cigarette smoke-driven inflammation in human macrophages.
Highlights
Chronic obstructive pulmonary disease (COPD) is a syndrome characterized by progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma, which is due predominantly to chronic cigarette smoking [1]
Since it has been reported that exposure to cigarette of macrophages stimulates release of different pro-inflammatory cytokines, including IL-8 [36] we measured the effect of different concentrations of cigarette smoke extract (CSE) on intracellular IL-8 production in THP-1 cells incubated for 6 h and 24 h (Fig. 1A)
B-carotene has been reported to arrest the increase in IL-6 and IL-8 induced by a long-term cigarette smoke exposition in serum, bronchoalveolar lavage fluid and lung tissue of rats [57]
Summary
Chronic obstructive pulmonary disease (COPD) is a syndrome characterized by progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma, which is due predominantly to chronic cigarette smoking [1]. Chronic exposure to cigarette smoke activates an inflammatory cascade in the airways resulting in the production of a number of cytokines and chemokines, with accompanying damage to the lung epithelium and increased vascular permeability and recruitment of macrophages and neutrophils [2,3]. Bronchoalveolar lavage (BAL) fluid from smokers compared to nonsmokers show a five-fold increase in the number of inflammatory cells in the lung, of which 85–90% are alveolar macrophages. Increased levels of IL-8 have been found in induced sputum [11] and bronchoalveolar lavage from patients with smokingrelated COPD associated with increased numbers of activated neutrophils [12]. IL-8 has been implicated in the initiation and maintenance of chronic airway inflammation induced by cigarette smoke
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