Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E₂ Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades

Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.