CONSTITUTIVE PRODUCTION OF INFLAMMATORY AND MITOGENIC CYTOKINES BY RHEUMATOID SYNOVIAL FIBROBLASTS

Conditioned media obtained from fibroblasts cultured from rheumatoid and certain other inflammatory synovia were observed to stimulate [H-3]thymidine incorporation in an indicator murine fibroblast line. Synovial fibroblasts derived from the joints of patients with osteoarthritis did not display this property. This effect persisted in culture for many weeks and occurred in the absence of co-stimulatory immune cells. Antibody neutralization studies implicated a role for basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), granulocyte/macrophage colony-stimulating factor (GM-CSF), and interleukin 1-beta (IL-1-beta) in the increased proliferative activity of synovial fibroblast-conditioned media. Synovial cell synthesis of bFGF, TGF-beta-1, GM-CSF, IL-1-beta, and IL-6 was confirmed by S-35-methionine labeling and immunoprecipitation. The constitutive production of inflammatory and mitogenic cytokines by synovial fibroblasts may represent the result of long-term, phenotypic changes that occurred in vivo. Persistent cytokine production by synovial fibroblasts may play an important role in the continued recruitment and activation of inflammatory cells in chronic arthritis and in the formation of rheumatoid pannus.