PGE2 contributes to the pathogenesis of several chronic

inflammatory conditions, including periodontitis, RA and cardiovascular inflammatory disease. High concentrations of PGE2 have been FG-4592 supplier detected in the synovial fluid of patients with OA and RA [82] and [83]. PGE2 has also been found in TMJ synovial fluids from patients with ID, and is associated with synovitis index based on synovial membrane hyperemia as the diagnostic criteria for TMJ arthroscopy [84] and [85]. It has been reported that cytokine-activated cells, such as synovial cells, chondrocytes and macrophages/monocytes, are the primary source of PGE2 in arthritic joints. PGE2 production at sites of inflammation coincides with the up-regulation of COX-2 expression in articular cells activating pro-inflammatory factors [86]. The existence of four EP receptor subtypes (EP1–4) encoded by distinct genes also contributes to the diversity of the biological activity of PGE2[87]. EP1 acts largely by increasing calcium flux but perhaps also via protein kinase C (PKC) [88]. Although it might be coupled to Gq, the absence of a PD-1/PD-L1 inhibitor phosphatidylinositide response has led to speculation that it is coupled to an as yet unidentified G protein [87]. Both

EP2 and EP4 are coupled to Gs and stimulate cyclic 3,5-adenosine monophosphate (cAMP) formation [89] and [90]. EP3 is coupled to Gi and acts largely by inhibiting cAMP production [91]. FLS from patients with RA and OA mainly expressed EP2 and EP4 [92]. A previous study has shown that PGE2 increased the production of pro-inflammatory cytokines such as IL-6 and VEGF

in FLS with RA and OA through the activation of EP2 and EP4, and with increases in cAMP [92]. These findings suggest that elevated PGE2 production is associated with inflammatory joint diseases, and can lead to bone loss. On microarray analysis, EP2 and EP4 were expressed in FLS from patients with ID TMJ, and the expression of EP2 and EP4 was slightly elevated in FLS treated with IL-1β or TNF-α (Table 3). The agonists of EP2 and EP4, and PGE2 stimulate the production of IL-6 in FLS (Fig. 4) [19]. EP4 receptor was partially effective with regard to IL-6 production in FLS mediated by PGE2, as indicated by treatment with EP4 tetracosactide agonist. Expression of EP4 receptor was at a lower level than that of the EP2 receptor (Table 3), and was transiently enhanced by IL-1β [19]. PGE2 affects IL-6 production through EP2 and EP4 in the FLS. In addition, COX inhibitors (indomethacin or celecoxib) decreased the expression of IL-6 in FLS stimulated with IL-1β (Fig. 5) [19]. Our results suggest that COX inhibitors as non-steroidal anti-inflammatory drugs (NSAIDs) are useful for treating synovitis in TMJ through the suppression of both PGE2 and inflammatory mediators such as IL-6.