Levels of prostaglandin E2 (PGE2) and its processing enzyme, prostaglandin-endoperoxide-synthase-2/ cyclooxygenase-2 (PTGS2/COX-2), are elevated in actively progressing periodontal lesions, but suppressed in chronic disease. COX-2 expression is regulated through inflammatory signaling that converges on the mitogen-activated protein kinase (MAPK) pathway. Emerging evidence suggests a role for the inflammatory adaptor protein, ASC/Pycard, in MAPK activation. We postulated that ASC may represent a mediator of the MAPK-mediated regulatory network of PGE2 production. Using RNAi-mediated gene slicing, we demonstrated that ASC regulates COX-2 expression and PGE2 production in THP1 monocytic cells following infection with Porphyromonas gingivalis (Pg). Production of PGE2 did not require the inflammasome adaptor function of ASC, but was dependent on MAPK activation. Furthermore, the MAP kinase kinase kinase CARD domain-containing protein RIPK2 was induced by Pg in an ASC-dependent manner. Reduced ASC and RIPK2 levels were revealed by orthogonal comparison of the expression of the RIPK family in ASC-deficient THP1 cells with that in chronic periodontitis patients. We show that pharmacological inhibition of RIPK2 represses PGE2 secretion, and RNAi-mediated silencing of RIPK2 leads to diminished MAPK activation and PGE2 secretion. These findings identify a novel ASC-RIPK2 axis in the generation of PGE2 that is repressed in patients diagnosed with chronic adult periodontitis
