title: Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice.
abstract: BACKGROUND
  Biological drugs are effective in patients with rheumatoid arthritis (RA), but increase severe infections. The CC chemokine receptor (CCR) 9 antagonist was effective for Crohn's disease without critical adverse effects including infections in clinical trials. The present study was carried out to explore the pathogenic roles of chemokine (C-C motif) ligand (CCL) 25 and its receptor, CCR9, in autoimmune arthritis and to study if the CCR9 antagonist could be a new treatment for RA.
  
  
  METHODS
  CCL25 and CCR9 expression was examined with immunohistochemistry and Western blotting. Concentration of interleukin (IL)-6, matrix metalloproteinase (MMP)-3 and tumor necrosis factor (TNF)-α was measured with enzyme-linked immunosorbent assays. Effects of abrogating CCR9 on collagen-induced arthritis (CIA) was evaluated using CCR9-deficient mice or the CCR9 antagonist, CCX8037. Fluorescence labeled-CD11b+ splenocytes from CIA mice were transferred to recipient CIA mice and those infiltrating into the synovial tissues of the recipient mice were counted.
  
  
  RESULTS
  CCL25 and CCR9 proteins were found in the RA synovial tissues. CCR9 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and dendritic cells in the synovial tissues. Stimulation with CCL25 increased IL-6 and MMP-3 production from RA FLS, and IL-6 and TNF-α production from peripheral blood monocytes. CIA was suppressed in CCR9-deficient mice. CCX8037 also inhibited CIA and the migration of transferred CD11b+ splenocytes into the synovial tissues.
  
  
  CONCLUSIONS
  The interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production. Blocking CCL25 or CCR9 may represent a novel safe therapy for RA.
authors.forename: Waka
authors.initials: W
authors.lastname: Yokoyama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kaneko
authors.forename: Matthew
authors.initials: M
authors.lastname: Walters
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: Yoshishige
authors.initials: Y
authors.lastname: Miyabe
authors.forename: Paul E
authors.initials: PE
authors.lastname: Love
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Kaori
authors.initials: K
authors.lastname: Watanabe-Imai
authors.forename: Trevor T
authors.initials: TT
authors.lastname: Charvat
authors.forename: Mark Et
authors.initials: ME
authors.lastname: Penfold
authors.forename: Juan
authors.initials: J
authors.lastname: Jaen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Harigai
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D054388:Receptors, CCR / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C119309:CC chemokine receptor 9; C491541:Ccl25 protein, mouse; D019742:Chemokines, CC; D015850:Interleukin-6; D054388:Receptors, CCR; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; D019278:Matrix Metalloproteinase 3