Amelioration of rat adjuvant-induced arthritis by Met-RANTES

  • Arthritis Rheum. 2005 Jun;52(6):1907-19. doi: 10.1002/art.21033.
Shiva Shahrara  1 ,  Amanda E I Proudfoot ,  James M Woods ,  Jeffrey H Ruth ,  M Asif Amin ,  Christy C Park ,  Christian S Haas ,  Richard M Pope ,  G Kenneth Haines ,  Yuan Yuan Zha ,  Alisa E Koch
Affiliations
  • 1. Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. [email protected]
PMID: 15934086 DOI: 10.1002/art.21033
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.

Conclusion: The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.

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