A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE(2) by a mechanism dependent on COX-2, mPGES-1 and iPLA(2)s. BaP1 also induces IL-1 beta release, which up-regulates the production of PGE(2) at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-kappa B pathway. While NF-kappa B p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1-nduced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE(2) triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE(2) biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes.