title: Effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on the expression of inflammatory cytokines and apoptosis induction in rheumatoid synovial fibroblasts and monocytes.
abstract: This study was performed to investigate whether peroxisome proliterator-activated receptor-gamma (PPAR-gamma) exerted an anti-inflammatory effect on rheumatoid synovial cells and inhibited dysregulated proliferation. The expression of PPAR-gamma mRNA in cultured human synoviocytes and THP-1 cells was analysed by RT-PCR. PPAR-gamma was expressed in normal, osteoarthritis (OA), rheumatoid arthritis (RA) synovial cells as well as a human monocytic cell line, THP-1. In RA and OA synoviocytes, the induction of inflammatory cytokine mRNA expression such as TNF-alpha and IL-1beta was significantly inhibited by the natural PPAR-gamma agonist, 15 deoxy-Delta(12,14)prostaglandin J(2)(15d-PGJ(2)). The effect of PPAR-gamma on the nuclear factor (NF)-kappaB activity was tested by electrophoretic mobility shift assay (EMSA). Both troglitazone and 15d-PGJ(2)markedly inhibited TNF-alpha-induced NF-kappaB activation at 30 microM. However, PPAR-gamma agonist neither reduced proliferation nor induced apoptosis in RA synoviocytes when measured by XTT assay and fluorescence activated cell sorter (FACS) analysis. In contrast, it induced apoptosis in a dose-dependent manner in THP-1 cells and augmented TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well. In conclusion, these data demonstrate that PPAR-gamma is expressed in human synoviocytes and THP-1 cells, and the PPAR-gamma activation inhibits expression of inflammatory cytokines in RA synoviocytes. Furthermore, PPAR-gamma activation induces apoptosis by itself and augments TRAIL/Apo2L-induced apoptosis in THP-1 cells. These results suggest that PPAR-gamma agonists may provide a new therapeutic approach for RA.
authors.affiliation: Department of Biochemistry, Korea University College of Medicine, Sungbuk-Gu, Seoul, Korea.
authors.forename: J D
authors.initials: JD
authors.lastname: Ji
authors.forename: H
authors.initials: H
authors.lastname: Cheon
authors.forename: J B
authors.initials: JB
authors.lastname: Jun
authors.forename: S J
authors.initials: SJ
authors.lastname: Choi
authors.forename: Y R
authors.initials: YR
authors.lastname: Kim
authors.forename: Y H
authors.initials: YH
authors.lastname: Lee
authors.forename: T H
authors.initials: TH
authors.lastname: Kim
authors.forename: I J
authors.initials: IJ
authors.lastname: Chae
authors.forename: G G
authors.initials: GG
authors.lastname: Song
authors.forename: D H
authors.initials: DH
authors.lastname: Yoo
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Sohn
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008830:Microbodies / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha