title: Stimulatory role of lysophosphatidic acid in cyclooxygenase-2 induction by synovial fluid of patients with rheumatoid arthritis in fibroblast-like synovial cells.
abstract: 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.
authors.affiliation: Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nochi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tomura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tobo
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shinozaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagishi
authors.forename: Hideo
authors.initials: H
authors.lastname: Ohta
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
authors.forename: Koichi
authors.initials: K
authors.lastname: Tamoto
mesh_terms: 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*
chemical_list: 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