Introduction
The synovial tissue in rheumatoid arthritis (RA) contains synovial fibroblasts and stromal cells as well as macrophages. Synovial stromal cells and fibroblasts are thought to proliferate in situ [1]. On the contrary, macrophages do not proliferate, but rather differentiate from monocytes that migrated from the peripheral blood, and are activated to differentiate in the synovial tissue. Macrophages in RA synovium secrete many inflammatory mediators (IL-1, IL-6, IL-8, tumor necrosis factor-α [TNF-α] and PGE2) and a variety of matrix metalloproteinases, and are thought to play a central role in the inflammation and joint destruction characteristic of RA [2]. The number of macrophages in RA synovium correlates significantly with clinical symptoms and the degree of joint damage [3]. Understanding the regulation of macrophage accumulation in the RA synovium should therefore provide insight into the inflammatory nature of rheumatoid synovitis.
Migration of peripheral blood monocytes is likely to be influenced by chemokines. A number of chemokines, including IL-8, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-1β, epithelial-derived neutrophil attractant 78, and regulated upon activation, normal T cell expressed and secreted (RANTES), are known to be found in RA synovial fluid [4,5,6,7,8]. A number of specific chemokine receptors including CCR1, CCR2, CCR5, CCR8, and CXCR4 are also known to be expressed by peripheral blood monocytes [9,10]. Despite this information, the specific chemokine–chemokine receptor interactions involved in the recruitment of monocytes into the rheumatoid synovium have not been fully delineated.
To address this issue, we examined chemokine receptor expression by peripheral blood monocytes, and also analyzed the capacity of supernatants from RA synovial stromal cells to induce monocyte migration. The data indicate that MCP-1 secreted by synovial stromal cells plays a major role in attracting monocytes to the synovium, and that IL-8 may also contribute.