β1 integrin–mediated signaling induces intercellular adhesion molecule 1 and Fas on rheumatoid synovial cells and Fas‐mediated apoptosis

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Abstract
Objective Rheumatoid arthritis (RA) synovial cells interact with inflammatory cells, as well as extracellular matrices, through integrins. However, the relevance of β1 integrin to inflammatory processes in RA remains unclear. We examined the role of β1 integrin–mediated signaling in RA. Methods Expression of cell‐surface molecules was assessed by FACScan. Engagement of β1 integrins was performed by crosslinking using a specific monoclonal antibody (mAb) and ligand matrices such as fibronectin or collagen. To determine the involvement of tyrosine kinases in β1 integrin–mediated signaling, the cells were pretreated with various inhibitors of intracytoplasmic signaling or were transfected with a wild‐type focal adhesion kinase (FAK) or a dominant negative truncation of the FAK expression plasmid via cationic liposome‐mediated transfection. Apoptosis of synovial cells was detected by double staining with propidium iodide and annexin V. Results β1 integrin was highly expressed on RA synovial cells. Engagement of β1 integrins by crosslinking as well as by ligand matrices markedly up‐regulated expression of intercellular adhesion molecule 1 (ICAM‐1) and Fas. Up‐regulation of ICAM‐1 and Fas induced by β1 integrin was mediated by the tyrosine kinase signaling pathway, especially involving FAK. Fas‐mediated early apoptotic change in the cells was amplified by β1 crosslinking. Conclusion Our results suggest that interaction of β1 integrins with extracellular matrix augments expression of ICAM‐1 and Fas on RA synovial cells, as well as Fas‐mediated apoptosis of synovial cells. This might lead to the spontaneous growth arrest through the Fas/Fas ligand pathway observed in RA synovitis.