Modulation of MMP-9 pathway by lycopene in macrophages and fibroblasts exposed to cigarette smoke.
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.
Institute of General Pathology, Catholic University School of Medicine, L. Go F. Vito, 100168 Rome, Italy. p.palozza@rm.unicatt.it
Paola
P
Palozza
Rossella E
RE
Simone
Assunta
A
Catalano
Flavia
F
Saraceni
Leonardo
L
Celleno
Maria Cristina
MC
Mele
Giovanni
G
Monego
Achille
A
Cittadini
D000818:Animals; D002338:Carotenoids / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D000077276:Lycopene; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism
D002338:Carotenoids; D020780:Matrix Metalloproteinase 9; D000077276:Lycopene