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* Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611;
Geneva Research Centre Merck Serono International S.A., Geneva, Switzerland;
Department of Microbiology & Immunology, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, IL 60515;
Department of Pathology, Yale University School of Medicine, New Haven, CT 06511;
¶ Saint Francis Hospital, Resurrection, Evanston, IL 60202; and
|| University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093
Chemokines, including RANTES/CCL5 and MCP-1/CCL2, are highly expressed in the joints of patients with rheumatoid arthritis, and they promote leukocyte migration into the synovial tissue. This study was conducted to determine whether the inhibition of RANTES and MCP-1 therapeutically was capable of ameliorating rat of adjuvant-induced arthritis (AIA). Postonset treatment of AIA using a novel inhibitor for endogenous MCP-1 (P8A-MCP-1) improved clinical signs of arthritis and histological scores measuring joint destruction, synovial lining, macrophage infiltration, and bone erosion. Using immunohistochemistry, ELISA, real-time RT-PCR, and Western blot analysis, we defined joint inflammation, bony erosion, monocyte migration, proinflammatory cytokines, and bone markers, and p-p38 levels were reduced in rat AIA treated with P8A-MCP-1. In contrast, neither the dominant-negative inhibitor for endogenous RANTES (44AANA47-RANTES) nor the CCR1/CCR5 receptor antagonist, methionylated-RANTES, had an effect on clinical signs of arthritis when administered after disease onset. Additionally, therapy with the combination of 44AANA47-RANTES plus P8A-MCP-1 did not ameliorate AIA beyond the effect observed using P8A-MCP-1 alone. Treatment with P8A-MCP-1 reduced joint TNF-
, IL-1β, and vascular endothelial growth factor levels. P8A-MCP-1 also decreased p38 MAPK activation in the joint. Our results indicate that inhibition of MCP-1 with P8A-MCP-1 after the onset of clinically detectable disease ameliorates AIA and decreases macrophage accumulation, cytokine expression, and p38 MAPK activation within the joint.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AR049353 (to S.S.) and AR049217 and AR048269 (to R.M.P.).
2 Address correspondence and reprint requests to Dr. Shiva Shahrara, Northwestern University Feinberg School of Medicine, Department of Medicine, Section of Rheumatology, McGaw Pavilion, 240 East Huron, Suite 2220, Chicago, IL 60611. E-mail address: s-shahrara{at}northwestern.edu
3 Abbreviations used in this paper: ST, synovial tissue; AI, articular index; AIA, adjuvant-induced arthritis; CIA, collagen-induced arthritis; MMP-9, matrix metalloproteinase-9; p, phosphorylated; RANKL, receptor activator of NF-
B ligand; VEGF, vascular endothelial growth factor; Met-RANTES, methionylated-RANTES.
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