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* Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan;
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan;
Rheumatology Unit, Sapporo Gorinbashi Orthopedic Hospital in Gorinbashi Hospitals, Sapporo, Hokkaido, Japan;
Department of Orthopedic Surgery, Gunma Graduate University School of Medicine, Gunma, Japan; and
¶ Research Laboratory, Kirin Brewery, Takasaki, Japan
While inflammatory cytokines are well-recognized critical factors for the induction of cyclooxygenase-2 (COX-2) in activated fibroblast-like synovial cells, the roles of biologically active components other than inflammatory cytokines in synovial fluid remain unknown. Herein, we assessed the role of lysophosphatidic acid (LPA), a pleiotropic lipid mediator, in COX-2 induction using synovial fluid of patients with rheumatoid arthritis (RA) in fibroblast-like RA synovial cells. Synovial fluid from RA patients stimulated COX-2 induction, which was associated with prostaglandin E2 production, in RA synovial cells. The synovial fluid-induced actions were inhibited by Gi/o protein inhibitor pertussis toxin and LPA receptor antagonist 3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid (Ki16425). In fact, LPA alone significantly induced COX-2 expression and enhanced IL-1
- or IL-1β-induced enzyme expression in a manner sensitive to pertussis toxin and Ki16425. RA synovial cells abundantly expressed LPA1 receptor compared with other LPA receptor subtypes. Moreover, synovial fluid contains a significant amount of LPA, an LPA-synthesizing enzyme autotaxin, and its substrate lysophosphatidylcholine. In conclusion, LPA existing in synovial fluid plays a critical role in COX-2 induction in collaboration with inflammatory cytokines in RA synovial cells. Ki16425-sensitive LPA receptors may be therapeutic targets for RA.
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1 This work was supported by a grants-in-aid for scientific research from the Japan Society for the Promotion of Science; a grant from the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and grants from the Yamanouchi Foundation for Research on Metabolic Disorders, the Uehara Memorial Foundation, and the Takeda Science Foundation.
2 Current address: Rheumatology Unit, Motomachi Orthopedic Hospital, Sapporo, Hokkaido 065-0021, Japan.
3 Address correspondence and reprint requests to Dr. Koichi Tamoto, Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa 769-2193, Japan. E-mail address: tamotok{at}kph.bunri-u.ac.jp or Dr. Fumikazu Okajima, Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. E-mail address: fokajima{at}showa.gunma-u.ac.jp
4 Abbreviations used in this paper: RA, rheumatoid arthritis; RANKL, receptor activator of NF-
B ligand; COX-2, cyclooxygenase-2; IL, interleukin; PGE2, prostaglandin E2; Ki16425, 3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid; LPA, lysophosphatidic acid; S1P, sphingosine 1-phosphate; PTX, pertussis toxin; LPC, lysophosphatidylcholine; MG lipase, monoglyceride lipase; DGPP, dioctyl glycerol pyrophosphate.
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