Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice.
Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.
Plater-Zyberk
C
C
Geneva Biomedical Research Institute, Glaxo Wellcome R&D S.A., Switzerland. CPZ24438@GGR.CO.UK
Hoogewerf
A J
AJ
Proudfoot
A E
AE
Power
C A
CA
Wells
T N
TN
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000031:analogs & derivatives*; D018925:Chemokines / Q000627:therapeutic use*; D003094:Collagen; D004195:Disease Models, Animal; D006801:Humans; D007596:Joints / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012720:Severity of Illness Index; D015854:Up-Regulation
D018946:Chemokine CCL5; D018925:Chemokines; C108335:RANTES, Met-; D018121:Receptors, Cytokine; D003094:Collagen