title: Chemerin activates fibroblast-like synoviocytes in patients with rheumatoid arthritis.
abstract: BACKGROUND
  Chemerin is a chemotactic agonist identified as a ligand for ChemR23 that is expressed on macrophages and dendritic cells (DCs). In this study, we analyzed the expression of chemerin and ChemR23 in the synovium of rheumatoid arthritis (RA) patients and the stimulatory effects of chemerin on fibroblast-like synoviocytes (FLSs) from RA patients.
  
  
  METHODS
  Chemerin and ChemR23 expression in the RA synovium was ascertained by immunohistochemistry and Western blot analysis. Chemerin expression on cultured FLSs was analyzed by ELISA. ChemR23 expression on FLSs was determined by immunocytochemistry and Western blot analysis. Cytokine production from FLSs was measured by ELISA. FLS cell motility was evaluated by utilizing a scrape motility assay. We also examined the stimulating effect of chemerin on the phosphorylation of mitogen-activated protein kinase (MAPK), p44/42 mitogen-activated protein kinase (ERK1/2), p38MAPK, c-Jun N-terminal kinase (JNK)1/2 and Akt, as well as on the degradation of regulator of NF-κB (IκBα) in FLSs, by Western blot analysis.
  
  
  RESULTS
  Chemerin was expressed on endothelial cells and synovial lining and sublining cells. ChemR23 was expressed on macrophages, immature DCs and FLSs and a few mature DCs in the RA synovium. Chemerin and ChemR23 were highly expressed in the RA synovium compared with osteoarthritis. Chemerin and ChemR23 were expressed on unstimulated FLSs. TNF-α and IFN-γ upregulated chemerin production. Chemerin enhanced the production of IL-6, chemokine (C-C motif) ligand 2 and matrix metalloproteinase 3 by FLSs, as well as increasing FLS motility. The stimulatory effects of chemerin on FLSs were mediated by activation of ERK1/2, p38MAPK and Akt, but not by JNK1/2. Degradation of IκB in FLSs was not promoted by chemerin stimulation. Inhibition of the ERK1/2, p38MAPK and Akt signaling pathways significantly suppressed chemerin-induced IL-6 production. Moreover, blockade of the p38MAPK and Akt pathways, but not the ERK1/2 pathway, inhibited chemerin-enhanced cell motility.
  
  
  CONCLUSIONS
  The interaction of chemerin and ChemR23 may play an important role in the pathogenesis of RA through the activation of FLSs.
authors.affiliation: Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kaneko
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Miyabe
authors.forename: Aiko
authors.initials: A
authors.lastname: Takayasu
authors.forename: Shin
authors.initials: S
authors.lastname: Fukuda
authors.forename: Chie
authors.initials: C
authors.lastname: Miyabe
authors.forename: Masashi
authors.initials: M
authors.lastname: Ebisawa
authors.forename: Waka
authors.initials: W
authors.lastname: Yokoyama
authors.forename: Kaori
authors.initials: K
authors.lastname: Watanabe
authors.forename: Toshio
authors.initials: T
authors.lastname: Imai
authors.forename: Kenzo
authors.initials: K
authors.lastname: Muramoto
authors.forename: Yuya
authors.initials: Y
authors.lastname: Terashima
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sugihara
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology*
chemical_list: C102741:CMKLR1 protein, human; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D019707:Receptors, Chemokine