title: Amelioration of rat adjuvant-induced arthritis by Met-RANTES.
abstract: OBJECTIVE
  CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein 1alpha (MIP-1alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat.
  
  
  METHODS
  Using immunohistochemistry, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA.
  
  
  RESULTS
  Administration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that Met-RANTES inhibited MIP-1alpha and MIP-1beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor alpha, interleukin-1beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint.
  
  
  CONCLUSIONS
  The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-shahrara@northwestern.edu
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
authors.forename: Amanda E I
authors.initials: AE
authors.lastname: Proudfoot
authors.forename: James M
authors.initials: JM
authors.lastname: Woods
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Ruth
authors.forename: M Asif
authors.initials: MA
authors.lastname: Amin
authors.forename: Christy C
authors.initials: CC
authors.lastname: Park
authors.forename: Christian S
authors.initials: CS
authors.lastname: Haas
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Zha
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019742:Chemokines, CC / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051381:Rats; D019707:Receptors, Chemokine / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D018946:Chemokine CCL5; D019742:Chemokines, CC; C108335:RANTES, Met-; D019707:Receptors, Chemokine