Background: Matrix metalloproteinases (MMPs) are the enzymes degrading extracellular matrix components. They are involved in many physiological and pathological processes including embryonic development, morphogenesis, wound healing, angiogenesis and cancer matastasis. MMP-1 is a collagenase mainly associated with a tumor metastasis in humans. Its expression as well as activity can be upregulated by reactive oxygen species (ROS), hence the heme oxygenease (HO-1), which is known to be the anti-inflammatory and anti-oxidative enzyme, could potentially downregulate MMP-1 activity and expression.

Methods and results: In order to find the interactions between human MMP-1 and HO-1 levels we utilised human lung cancer cell line NCI-H292 stably or transiently overexpressing HO-1. Stable transfection was done by pcDNA-HO-1 plasmid, harboring the neomycin resistance gene, and stably modified cells were achieved by culturing in the presence of G418. Transient overexpression was obtained by transduction of NCI-H292 cells with adenoviral vectors containing HO-1. Control cells were treated with empty plasmid or adenoviral vector with reporter, lacZ gene. Gene expression was confirmed by real-time RT-PCR and Western. The results revealed that overexpression of HO1 downregulated MMP-1 transcripts. Additionally, the level of MMP-13, which is considered as a murine functional analogue of human MMP-1 was checked in murine primary fibroblasts and macrophages. The fibroblasts were isolated from the skin of animals with different HO-1 genotypes (HO1+/+ and HO1 -/-), while macrophages were differentiated from bone marrow- derived monocytes. Interestingly, it turned out that MMP-13 is downregulated in cells of HO1-/- genotype, both in fibroblasts and macrophages. In macrophages we have also checked the level of some anti-oxidant genes and found out that expression of catalase is upregulated, while the transcription of SOD2, glutatione transferase and ferritin is downregulated in cells derived from HO-1-/- mice .

Conclusions: Either stable or transient overexpression of HO-1 in NCI-H292 cells downregulates MMP-1. On the other hand, MMP-13 was decreased in murine cells completely devoid of HO-1 (HO1-/-) which may result from the compensatory upregulation of the other anti-oxidant genes. However, the exact mechanism needs further investigations.

The work was supported by grant PBZ- KBN 107/P04/2004

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