The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to bone and cartilage destruction. A substantial body of evidence suggests that prostaglandin E2 (PGE2) contributes to the pathogenesis of RA, and nonsteroidal anti-inflammatory drugs, inhibitors of the synthesis of PGE2 and other prostanoids, continue to be used in the treatment of this disease. To begin to understand the mechanism by which prostaglandins modulate the pathophysiology of this disease, we examined mice lacking each of the four known PGE2 (EP) receptors after generation of collagen antibody–induced arthritis, an animal model of RA. Homozygous deletion of the EP1, EP2, or EP3 receptors did not affect the development of arthritis, whereas EP4 receptor–deficient mice showed decreased incidence and severity of disease. These animals also showed reduced inflammation as assessed by circulating IL-6 and serum amyloid A levels. Joint histopathology of EP4–/– animals revealed reduced bone destruction, proteoglycan loss, and type II collagen breakdown in cartilage compared with EP4+/+ mice. Furthermore, liver and macrophages isolated from EP4–/– animals produced significantly less IL-1β and IL-6 than control samples. Thus, PGE2 contributes to disease progression at least in part by binding to the EP4 receptor. Antagonists of this receptor might therefore provide novel agents for the treatment of RA

The novel phospho‐non‐steroidal anti‐inflammatory drugs, OXT‐328, MDC‐22 and MDC‐917, inhibit adjuvant‐induced arthritis in rats

“…PGE 2 , an important proinflammatory eicosanoid, is involved in the pathogenesis of arthritis (McCoy et al ., 2002). We evaluated the effect of phospho‐aspirin, aspirin, phospho‐sulindac and phospho‐ibuprofen on the production of PGE 2 by NIH 3T3 cells, both under baseline conditions and following stimulation with the calcium ionophore A23187 (Hyman et al ., 1982).…”

Inhibition of COX‐2‐mediated eicosanoid production plays a major role in the anti‐inflammatory effects of the endocannabinoid N‐docosahexaenoylethanolamine (DHEA) in macrophages

“…In TLR4 stimulated glomerular mesangial cells, PGE 2 modulated NO production mainly occurred in a cAMP‐dependent manner through the EP 4 receptor (Lin et al ., ). PGE 2 was also found to be capable of controlling the production of IL‐6 via EP 4 in macrophages, in an animal model of rheumatoid arthritis (McCoy et al ., ), and in different cell types. For MCP‐1 it was found that in the process of macrophage migration, activated PGE 2 /EP 4 signalling up‐regulates its expression (Tajima et al ., ).…”

Eicosanoids and Respiratory Viral Infection: Coordinators of Inflammation and Potential Therapeutic Targets

“…PGE 2 augments IL-17 production and Th17 differentiation by increasing IL-23 production in T cells and dendritic cells [44,[50][51][52][53], an activity that likely occurs via EP2-and EP4mediated increases in cAMP [54,55]. Additionally, PGE 2 enhances the production of the proinflammatory cytokine IL-6 by leukocytes [56] and airway epithelial cells [57]. PGE 2 potently inhibits the production of a number of antimicrobial peptides (AMPs) such as human β-defensin by epithelial cells [58].…”