The Journal of Experimental Medicine
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Published online 30 January 2006 doi:10.1084/jem.20051310
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 325-335
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ARTICLE

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

Tetsuya Honda1,2, Eri Segi-Nishida1, Yoshiki Miyachi2, and Shuh Narumiya1

1 Department of Pharmacology and 2 Department of Dermatology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan

CORRESPONDENCE Shuh Narumiya: snaru{at}mfour.med.kyoto-u.ac.jp

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.

Abbreviations used: CAIA, collagen antibody–induced arthritis; CIA, collagen-induced arthritis; CII, type II collagen; COX, cyclooxygenase; FGF, fibroblast growth factor; H&E, hematoxylin and eosin; IP, prostacyclin receptor; MCP-1, monocyte chemoattractant protein 1; mPGES, microsomal prostaglandin E synthase; NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin; PGI, prostacyclin; RA, rheumatoid arthritis; RANKL, receptor activator of NF-{kappa}B ligand; VEGF, vascular endothelial growth factor.

T. Honda and E. Segi-Nishida contributed equally to this work.


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