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‐1β, 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.