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

• Published in: The Journal of immunology (1950) 2022-03, Vol.208 (5), p.1146
• Main Authors: Nakayama, Masaaki, Naito, Mariko, Omori, Kazuhiro, Ono, Shintaro, Nakayama, Koji, Ohara, Naoya
• Format: Article
• Language: English
• Subjects: Bacterial Proteins - genetics; Cell Line; Cyclooxygenase 2 - biosynthesis; Cysteine Endopeptidases - genetics; Dinoprostone - biosynthesis; Fimbriae Proteins - genetics; Gingipain Cysteine Endopeptidases - genetics; Gingipain Cysteine Endopeptidases - metabolism; Humans; I-kappa B Kinase - metabolism; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Monocytes - microbiology; Periodontitis - microbiology; Periodontitis - pathology; Porphyromonas gingivalis - metabolism; THP-1 Cells; Transcription Factor AP-1 - metabolism; Transcription Factor RelA - metabolism
• ISSN: 1550-6606
• DOI: 10.4049/jimmunol.2100866

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)/PGE , 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 , and used the wild-type strain and several gene-deletion mutants ( , , and ) to elucidate the involvement of gingipains in COX-2 expression and PGE 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 PGE 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/PGE 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/PGE production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from induce COX-2 expression and PGE 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.