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Modulation of MMP-9 pathway by lycopene in macrophages and fibroblasts exposed to cigarette smoke
Paola Palozza1, Rossella E Simone, Assunta Catalano
1Institute of General Pathology, Catholic University School of Medicine, L. Go F. Vito, 100168 Rome, Italy. p.palozza@rm.unicatt.it
Abstract:
Matrix metalloproteinase-9 (MMP-9) has been implicated in both inflammation and fibrosis. It has been reported that cigarette smoke induced MMP-9 expression and that lycopene may act as an anti-inflammatory agent and may counteract several signal pathways affected by cigarette smoke exposure. However, at the moment, it is unknown if lycopene may inhibit cigarette smoke-induced MMP-9 expression. Presently, we examined the inhibitory mechanism of lycopene on MMP-9 induction in cultured human macrophages (THP-1 cells), in isolated rat alveolar macrophages (AMs) and in cultured RAT-1 fibroblasts, all cellular sources of MMP-9, exposed to cigarette smoke extract (CSE). CSE induced a marked increase in MMP-9 expression in cultured as well as in isolated cells. A 8 h-lycopene pre-treatment (0.5-2 μM) reduced CSE-mediated MMP-9 induction in a dose- and time-dependent manner. Lycopene attenuated CSE-mediated activation of Ras, enhancing the levels of this protein in the cytosolic fraction. Moreover, lycopene inhibited CSE-induced ERK1/2 and NF-κB activation in a dose-dependent manner. Lycopene-mediated inhibition of MMP-9 was reversed by mevalonate and associated with a reduced expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Taken together, these results suggest that lycopene may inhibit CSE-mediated MMP-9 induction, primarily by blocking prenylation of Ras in a signaling pathway, in which MEK1/2-ERK1/2 and NF-κB are involved.
Insights
Lycopene inhibits cigarette smoke-induced matrix metalloproteinase-9 (MMP-9) expression in macrophages and fibroblasts. This inhibition occurs by blocking Ras prenylation, a key step in inflammatory signaling pathways.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Matrix metalloproteinase-9 (MMP-9) is linked to inflammation and fibrosis.
- Cigarette smoke extract (CSE) is known to increase MMP-9 expression.
- Lycopene exhibits anti-inflammatory properties and may counteract cigarette smoke effects.
Purpose of the Study:
- To investigate whether lycopene can inhibit MMP-9 induction caused by cigarette smoke exposure.
- To elucidate the underlying molecular mechanisms of lycopene's inhibitory action.
Main Methods:
- Cultured human macrophages (THP-1), rat alveolar macrophages (AMs), and RAT-1 fibroblasts were exposed to CSE.
- Cells were pre-treated with varying concentrations and durations of lycopene.
- MMP-9 expression, Ras activation, ERK1/2, NF-κB, and HMG-CoA reductase levels were analyzed.
Main Results:
- CSE significantly increased MMP-9 expression in all cell types.
- Lycopene pre-treatment dose- and time-dependently reduced CSE-induced MMP-9.
- Lycopene inhibited CSE-mediated activation of Ras, ERK1/2, and NF-κB.
- The inhibitory effect of lycopene was reversed by mevalonate and linked to reduced HMG-CoA reductase.
Conclusions:
- Lycopene effectively inhibits cigarette smoke extract-induced MMP-9 expression in various cell types.
- The primary mechanism involves blocking Ras prenylation within the MEK1/2-ERK1/2 and NF-κB signaling pathways.
- Lycopene represents a potential therapeutic agent against cigarette smoke-related inflammatory and fibrotic conditions.
