Intercellular adhesion molecule 1 underlies the functional heterogeneity of synovial cells in patients with rheumatoid arthritis: involvement of cell cycle machinery.
OBJECTIVE: To investigate whether synovial cells from rheumatoid arthritis (RA) synovium can be divided into 2 functionally different subpopulations: active or proliferative cells and apoptotic cells. METHODS: Expression of cell surface and cytoplasmic molecules on synovial cells was assessed by immunohistochemistry, flow cytometry, or Western blotting. Cells were categorized as intercellular adhesion molecule 1 (ICAM-1) positive or negative based on positive and negative selection of antibody-coated beads. Cell cycle and apoptosis were assessed using propidium iodide staining, TUNEL method, and DNA fragmentation. RESULTS: Expression of ICAM-1 and Fas was noted mainly in the synovial lining to sublining layer in vivo, and synovial cells could be clearly distinguished as ICAM-1 positive or negative. The expression of Fas was higher on ICAM-1-positive cells than on ICAM-1-negative cells in vitro. The functional and phenotypic heterogeneity between ICAM-1-positive and -negative cells was further emphasized by cell cycle machinery. The majority of ICAM-1-positive cells were arrested at the G0/G1 phase, whereas many of the ICAM-1-negative cells were at the S to G2/M proliferating phase. In ICAM-1-positive cells, p53 and p21 expression was up-regulated and cyclin-dependent protein kinase 6 activity was inhibited. Most ICAM-1-positive cells were apoptotic (as evidenced by TUNEL positivity and DNA fragmentation). ICAM-1-positive cells were induced not only by interleukin-1beta, but also by Fas crosslinking. CONCLUSION: ICAM-1-positive synovial cells represent growth arrest and subsequent apoptosis, whereas ICAM-1-negative cells are proliferative. Such differences in regulation of the cell cycle based on ICAM-1 status are important determinants of the lifespan, proliferation, and growth arrest of RA synoviocytes.