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.

Links

Publisher Full Text

Authors

Taxman DJ, Lei Y, Zhang S, Holley-Guthrie E, Offenbacher S, Ting JP

Institution

Department of Microbiology and Immunology, School of Medicine; University of North Carolina, Chapel Hill, NC, USA. debra_taxman@med.unc.edu

Source

Journal of dental research 91:9 2012 Sep pg 877-82

MeSH

Bacterial Proteins
CARD Signaling Adaptor Proteins
Cell Line, Tumor
Chronic Periodontitis
Cyclooxygenase 2
Cytoskeletal Proteins
Dinoprostone
Gene Expression Regulation, Enzymologic
Humans
Inflammation Mediators
MAP Kinase Kinase Kinases
MAP Kinase Signaling System
Porphyromonas gingivalis
RNA Interference
Receptor-Interacting Protein Serine-Threonine Kinase 2

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22828789