title: Adiponectin-mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is associated with increased production of adipokines, which are cytokine-like mediators that are produced mainly in adipose tissue but also in synovial cells. Since RA synovial fibroblasts (RASFs), lymphocytes, endothelial cells, and chondrocytes are key players in the pathophysiology of RA, this study was undertaken to analyze the effects of the key adipokine adiponectin on proinflammatory and prodestructive synovial effector cells.
  
  
  METHODS
  Lymphocytes were activated in part prior to stimulation. All cells were stimulated with adiponectin, and changes in gene and protein expression were determined by Affymetrix and protein arrays. Messenger RNA and protein levels were confirmed using semiquantitative reverse transcription-polymerase chain reaction (PCR), real-time PCR, and immunoassays. Intracellular signal transduction was evaluated using chemical signaling inhibitors.
  
  
  RESULTS
  Adiponectin stimulation of human RASFs predominantly induced the secretion of chemokines, as well as proinflammatory cytokines, prostaglandin synthases, growth factors, and factors of bone metabolism and matrix remodeling. Lymphocytes, endothelial cells, and chondrocytes responded to adiponectin stimulation with enhanced synthesis of cytokines and various chemokines. Additionally, chondrocytes released increased amounts of matrix metalloproteinases. In RASFs, adiponectin-mediated effects were p38 MAPK and protein kinase C dependent.
  
  
  CONCLUSIONS
  Our previous findings indicated that adiponectin was present in inflamed synovium, at sites of cartilage invasion, in lymphocyte infiltrates, and in perivascular areas. The findings of the present study indicate that adiponectin induces gene expression and protein synthesis in human RASFs, lymphocytes, endothelial cells, and chondrocytes, supporting the concept of adiponectin being involved in the pathophysiologic modulation of RA effector cells. Adiponectin promotes inflammation through cytokine synthesis, attraction of inflammatory cells to the synovium, and recruitment of prodestructive cells via chemokines, thus promoting matrix destruction at sites of cartilage invasion.
authors.affiliation: Justus-Liebig-University Giessen and Kerckhoff-Klinik, Bad Nauheim, Germany. e.neumann@kerckhoff-klinik.de
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Frommer
authors.forename: Birgit
authors.initials: B
authors.lastname: Zimmermann
authors.forename: Florian M P
authors.initials: FM
authors.lastname: Meier
authors.forename: Dirk
authors.initials: D
authors.lastname: Schröder
authors.forename: Matthias
authors.initials: M
authors.lastname: Heil
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffler
authors.forename: Christa
authors.initials: C
authors.lastname: Büchler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Steinmeyer
authors.forename: Fabia
authors.initials: F
authors.lastname: Brentano
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Ulf
authors.initials: U
authors.lastname: Müller-Ladner
authors.forename: Elena
authors.initials: E
authors.lastname: Neumann
mesh_terms: D052242:Adiponectin / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007719:Knee Joint / Q000503:physiopathology; D008214:Lymphocytes / Q000378:metabolism; D020370:Osteoarthritis, Knee; D040081:Protein Array Analysis; D013583:Synovial Membrane / Q000503:physiopathology*
chemical_list: D052242:Adiponectin; D018925:Chemokines