title: Decoy receptor 3 regulates the expression of tryptophan hydroxylase 1 in rheumatoid synovial fibroblasts.
abstract: Decoy receptor 3 (DcR3) is expressed in rheumatoid arthritis fibroblast‑like synoviocytes (RA‑FLS) and downregulates the expression of tryptophan hydroxylase 1 (TPH1), which is the rate‑limiting enzyme in serotonin synthesis. The aim of the present study was to determine the specificity of the effects of DcR3 on TPH1 in RA‑FLS, and therefore determine whether DcR3 had the potential to modulate the pathogenesis of RA. The present study also aimed to compare the effects of DcR3 and inflammatory cytokines on the expression of TPH1 in RA‑FLS and osteoarthritis (OA)‑FLS. Primary cultured RA‑ or OA‑FLS were incubated with 1.0 µg/ml DcR3‑Fc protein or 1.0 µg/ml control immunoglobulin G (IgG)1 for 12 h, or with 1.0 ng/ml tumor necrosis factor (TNF)α, 1.0 ng/ml interleukin (IL)‑1β or serum‑free Opti‑MEM only, for 24 h. The relative mRNA expression levels of TPH1 were subsequently quantified using reverse transcription‑polymerase chain reaction. The expression of serotonin in RA or OA synovial tissue was detected using immunohistochemistry. The mRNA expression of TPH1 was observed in both RA‑ and OA‑FLS and was significantly decreased following treatment with DcR3 in the RA‑FLS, however, not in the OA‑FLS. The mRNA expression of TPH1 was significantly decreased following treatment with TNFα or IL‑1β in both the RA‑ and OA‑FLS. The expression of serotonin in the multi‑layered lining synovial cells of RA and the outer layer lining synovial cells of OA was detected using immunohistochemistry. The present study is the first, to the best of our knowledge, to demonstrate that the expression of TPH1 in FLS is downregulated by inflammatory cytokines, and that DcR3 suppressed the expression of TPH1 in RA‑FLS in a disease‑specific manner. These results suggested that synovial serotonin may be involved in the pathogenesis of RA, and that TPH1 and DcR3 may be potential therapeutic targets for the treatment of RA.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo, Kobe, Hyogo 650‑0017, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo, Kobe, Hyogo 650‑0017, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo, Kobe, Hyogo 650‑0017, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo, Kobe, Hyogo 650‑0017, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Chuo, Kobe, Hyogo 650‑0017, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000235:genetics*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human; D012701:Serotonin; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase