Inhibition of matrix metalloproteinase-9 by interferons and TGF-beta1 through distinct signalings accounts for reduced monocyte invasiveness.

Cytokines may provide signals for regulating human monocyte matrix metalloproteinase-9 (MMP-9) activity. In this study, we investigated the roles of interferons (IFN) type I/II and transforming growth factor-beta1 (TGF-beta1) in MMP-9-mediated invasiveness. MMP-9 antibody and inhibitor, IFNs and TGF-beta1 inhibited monocyte transmigration through Matrigel. IFNs and TGF-beta1 downregulated MMP-9 mRNA, protein and activity levels. The inhibitory action of IFNs was associated with the STAT1/IRF-1 pathway since the JAK inhibitor AG490 blocked STAT1 phosphorylation, IRF-1 synthesis and counteracted the blockade of MMP-9 release. TGF-beta1-mediated MMP-9 inhibition appeared STAT1/IRF-1-independent but reversed by the protein tyrosine kinase inhibitor tyrphostin 25. Our data point out the importance of IFNs and TGF-beta1 in the control of monocyte MMP-9-mediated extravasation.