CYTOKINE INTERACTIONS PROMOTING DNA-SYNTHESIS IN HUMAN SYNOVIAL FIBROBLASTS

Objective. To evaluate in vitro cytokine combinations that may contribute to the pronounced hyperplasia often found in the joints of patients with rheumatoid arthritis. Methods. DNA synthesis, in the presence of various combinations of cytokines, was measured in vitro using low serum cultures of passaged synovial fibroblasts derived from nonrheumatoid tissue. Results. Coculture of synovial fibroblasts with platelet derived growth factor (PDGF) and fibroblast growth factor (FGF), at their respective optimal concentrations for DNA synthesis, led to a further increase. In combination with the described synovial fibroblast mitogen, interleukin 1 (IL-1), which can also generate a growth inhibitory cyclooxygenase product, the proliferative responses to PDGF, FGF, transforming growth factor alpha, and epidermal growth factor were enhanced; in some, but not in all of these fibroblast cultures containing IL-1, the achievement of maximal DNA synthesis required that the cyclooxygenase inhibitor, indomethacin, be included. Similar results were obtained when PDGF and FGF were cultured with tumor necrosis factor alpha (TNF alpha), and when IL-1 and TNF alpha were combined. The neuropeptide, substance P (10-(11)-10(-7)M), was inactive by itself and in the presence of IL-1. Conclusion. While cytokines individually may be activators of various signalling pathways in the synovial fibroblasts, it is when they are combined that they show their full potential as growth promoters, with possible ramifications for inflammatory joint disease.