Stimulatory role of lysophosphatidic acid in cyclooxygenase-2 induction by synovial fluid of patients with rheumatoid arthritis in fibroblast-like synovial cells.
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 E(2) production, in RA synovial cells. The synovial fluid-induced actions were inhibited by G(i/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-1alpha- or IL-1beta-induced enzyme expression in a manner sensitive to pertussis toxin and Ki16425. RA synovial cells abundantly expressed LPA(1) 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.
Nochi
Hiromi
H
Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan.
Tomura
Hideaki
H
Tobo
Masayuki
M
Tanaka
Nobuyuki
N
Sato
Koichi
K
Shinozaki
Tetsuya
T
Kobayashi
Tsutomu
T
Takagishi
Kenji
K
Ohta
Hideo
H
Okajima
Fumikazu
F
Tamoto
Koichi
K
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016207:Cytokines / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D004790:Enzyme Induction / Q000276:immunology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors; D013582:Synovial Fluid / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone; C032881:lysophosphatidic acid