A novel antagonist of the prostaglandin E-2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models

作者：Chen Q^*; Muramoto K; Masaaki N; Ding Y; Yang H; Mackey M; Li W; Inoue Y; Ackermann K; Shirota H; Matsumoto I; Spyvee M; Schiller S; Sumida T; Gusovsky F; Lamphier M

来源：British Journal of Pharmacology, 2010, 160(2): 292-310.

DOI：10.1111/j.1476-5381.2010.00647.x

• PGE(2)
• EP4 receptor
• EP4 antagonist
• Th1
• Th17
• IFN-gamma
• IL-17
• IL-23
• CIA
• GPI-induced arthritis model

Background and purpose:
Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E-2 (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP4 receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA.
Experimental approach:
Effects of PGE(2) and a novel EP4 receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat.
Key results:
Stimulation of the EP4 receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats.
Conclusion and implications:
PGE(2) stimulates EP4 receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP4 receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

• 出版日期2010-5