CXCR3 and CCR5 ligands in rheumatoid arthritis synovium.
The pathogenesis of rheumatoid arthritis (RA) may be mediated by Th1-type T cells. Since chemokine receptors CXCR3 and CCR5 are preferentially expressed on Th1 cells, we tested the expression and regulation of several chemokines, including those that signal through CXCR3 (interferon-gamma-inducible protein of 10 kDa, IP-10, CXCL10; and monokine induced by interferon-gamma, Mig, CXCL9) and CCR5 (macrophage inflammatory protein (Mip)-1 alpha, CCL3; and Mip-1 beta, CCL4) in RA synovial fluids, synovial tissues, and blood. Synovial fluid (SF) protein levels of IP-10 (32.1 +/- 10.5 ng/ml), Mig (15.0 +/- 6.4 ng/ml), Mip-1 beta (0.7 +/- 0.3 ng/ml), and Mip-1 alpha (0.8 +/- 0.1 ng/ml) were 100-, 50-, 25-, and 2-fold elevated in RASF compared to control SF (P < 0.001, P < 0.001, P < 0. 001, and P < 0.02, respectively). Tissue levels of IP-10, Mig, and Mip-1 beta were significantly higher in RA than in OA (P < 0.01). Serum levels of IP-10 (3.1 +/- 1.2 ng/ml) were higher in patients with seropositive RA compared to controls (1.2 +/- 0.2 ng/ml) (P < 0.02). There was a gradient of IP-10, Mig, Mip-1 alpha, and Mip-1 beta from the blood into the synovial fluid in RA. Infiltrating T cells around high endothelial venules in RA synovium and 90 +/- 3% of SF CD3(+)CD4(+) T cells expressed CXCR3, and 85 +/- 2% of SF CD3(+)CD4(+) T cells expressed CCR5. Chemokines, including IP-10, Mig, Mip-1 alpha, and Mip-1 beta, may participate in the selective recruitment of CCR5(+)CXCR3(+) T cells to the inflamed synovium.
Patel
D D
DD
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Zachariah
J P
JP
Whichard
L P
LP
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D018925:Chemokines / Q000097:blood; D006801:Humans; D019713:Receptors, CCR5 / Q000032:analysis*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000032:analysis*; D013583:Synovial Membrane / Q000737:chemistry*; D013601:T-Lymphocytes / Q000378:metabolism
C515187:CXCR3 protein, human; D018925:Chemokines; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine