Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

Prostaglandin (PG)I-2 (prostacyclin [PGI]) and PGE(2) are abundantly present in the synovial fluid of rheumatoid arthritis ( RA) patients. Although the role of PGE(2) in RA has been well studied, how much PGI(2) contributes to RA is little known. To examine this issue, we back-crossed 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 PGI(2)-IP and PGE(2)-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE(2) synthesis alone may not be sufficient for suppression of RA symptoms.