title: ASC-dependent RIP2 kinase regulates reduced PGE2 production in chronic periodontitis.
abstract: Levels of prostaglandin E(2) (PGE(2)) 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 PGE(2) production. Using RNAi-mediated gene slicing, we demonstrated that ASC regulates COX-2 expression and PGE(2) production in THP1 monocytic cells following infection with Porphyromonas gingivalis (Pg). Production of PGE(2) 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 PGE(2) secretion, and RNAi-mediated silencing of RIPK2 leads to diminished MAPK activation and PGE(2) secretion. These findings identify a novel ASC-RIPK2 axis in the generation of PGE(2) that is repressed in patients diagnosed with chronic adult periodontitis.
authors: Department of Microbiology and Immunology, School of Medicine; University of North Carolina, Chapel Hill, NC, USA. debra_taxman@med.unc.edu
authors: D J
authors: DJ
authors: Taxman
authors: Y
authors: Y
authors: Lei
authors: S
authors: S
authors: Zhang
authors: E
authors: E
authors: Holley-Guthrie
authors: S
authors: S
authors: Offenbacher
authors: J P-Y
authors: JP
authors: Ting
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D055113:Chronic Periodontitis / Q000201:enzymology* / Q000382:microbiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D016966:Porphyromonas gingivalis; D034622:RNA Interference; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; C402202:PYCARD protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020930:MAP Kinase Kinase Kinases; D015232:Dinoprostone