A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.
OBJECTIVE
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) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA.


METHODS
Effects of PGE(2) and a novel EP(4) 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.


RESULTS
Stimulation of the EP(4) 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.


CONCLUSIONS
PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.
Chen
Q
Q
Eisai Research Institute of Boston, Andover, MA, USA. qian_chen@eisai.com <qian_chen@eisai.com>
Muramoto
K
K
Masaaki
N
N
Ding
Y
Y
Yang
H
H
Mackey
M
M
Li
W
W
Inoue
Y
Y
Ackermann
K
K
Shirota
H
H
Matsumoto
I
I
Spyvee
M
M
Schiller
S
S
Sumida
T
T
Gusovsky
F
F
Lamphier
M
M
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D001552:Benzazepines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003094:Collagen; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects
D001552:Benzazepines; C549634:ER 819762; D007093:Imidazoles; C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases