MODULATION OF TNFSR(55) AND TNFSR(75) BY CYTOKINES AND GROWTH-FACTORS IN HUMAN SYNOVIAL FIBROBLASTS

Tumor necrosis factor alpha (TNF alpha) is suggested to be of importance in the pathogenesis of inflammatory diseases. One mechanism that modulates the action of TNF is binding to specific soluble receptors. Using human synovial fibroblasts, we investigated the effect of cytokines and growth factors, known to be present in increased amounts in arthritic disorders, on the release of the TNF soluble receptors TNFsR(75) and TNFsR(55). Levels of TNFsR(75) and TNFsR(55) were determined using conditioned medium from human synovial fibroblasts incubated in increasing concentrations of cytokines, IL-1 beta, TNF alpha, IL-6, and IL-2, and platelet derived growth factor BE (PDGF-BB), transforming growth factor beta (TGF beta), and insulin like growth factor I (IGF-I), alone or in combination with IL-1 beta. The levels of both TNFsR were measured by specific immunoassays. Both TNFsR demonstrated similar levels under basal conditions. IL-1 and TNF alpha induced a significant enhancement of TNFsR(75) compared to TNFsR(55). When cells were treated with both IL-1 beta and TNF alpha, a marked inhibition in the release of TNFsR(55) was observed, while TNFsR(75) did not show any changes, IL-6 and IL-2 produced no effect on the release of TNFsR(75) and a minimal increase of TNFsR(55), PDGF-BB and IGF-I demonstrated a dose dependent increased level of TNFsR(55), and both soluble receptors released were inhibited by TGF beta, TGF beta and IL-1 beta together produced a greater inhibition of the release of the TNFsR. These data support the notion that both TNFR in synovial fibroblasts are differently regulated.