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 c ells was assessed by immunohistochemistry, flow cytometry, or Western blott ing. Cells were categorized as intercellular adhesion molecule 1 (ICAM-1) p ositive or negative based on positive and negative selection of antibody-co ated beads. Cell cycle and apoptosis were assessed using propidium iodide s taining, TUNEL method, and DNA fragmentation. Results, Expression of ICAM-1 and Fas was noted mainly in the synovial lini ng to sublining layer in vivo, and synovial cells could be clearly distingu ished as ICAM-1 positive or negative, The expression of Fas was higher on I CAM-1-positive cells than on ICAM-1-negative cells in vitro. The functional and phenotypic heterogeneity between ICAM-1-positive and -negative cells w as further emphasized by cell cycle machinery. The majority of ICAM-1-posit ive cells were arrested at the G0/G1 phase, whereas many of the ICAM-1-nega tive cells were at the S to (G2/M proliferating phase. In ICAM-1-positive c ells, p53 and p21 expression was up-regulated and cyclin-dependent protein kinase 6 activity was inhibited. Most ICAM-1-positive cells were apoptotic las evidenced by TUNEL positivity and DNA fragmentation), ICAM-1-positive c ells were induced not only by interleukin-1 beta, but also by Fas crosslink ing. Conclusion. ICAM-1-positive synovial cells represent growth arrest and subs equent apoptosis, whereas ICAM-1-negative cells are proliferative. Such dif ferences in regulation of the cell cycle based on ICAM-1 status are importa nt determinants of the lifespan, proliferation, and growth arrest of RA syn oviocytes.