Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis.
Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP-/-) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP-/- mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.
Honda
Tetsuya
T
Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Segi-Nishida
Eri
E
Miyachi
Yoshiki
Y
Narumiya
Shuh
S
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism* / Q000502:physiology; D011464:Epoprostenol / Q000378:metabolism* / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D015850:Interleukin-6; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; C491910:Ptgir protein, mouse; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D003094:Collagen; D011464:Epoprostenol; D015232:Dinoprostone