Transforming Growth Factor β Stimulates Urokinase-Type Plasminogen Activator and DNA Synthesis, but not Prostaglandin E2Production, in Human Synovial Fibroblast

Transforming growth factor β (TGF-β) is usually associated with matrix formation and tissue repair; in contrast, cellular expression of the serine proteinase, urokinase-type plasminogen activator (u-PA) is often correlated with tissue remodeling, as well as with cell migration and transformation. We report here that purified recombinant human TGF-β (≥ 300 pg/ml) can stimulate rapidly (within 2 h) the u-PA activity of nonrheumatoid synovial fibroblast-like cells. As for interleukin 1 (IL-1), u-PA mRNA levels are raised in response to TGF-β, but unlike IL-1, no increase in prostaglandin E2levels occurs. In contrast to a number of other examples in the literature, in which these two cytokines have opposing actions, TGF-β can potentiate the action of optimal concentrations of IL-1 in enhancing u-PA expression. These effects of TGF-β are similar to those of all-trans-retinoic acid. In addition, synovial fibroblast DNA synthesis was stimulated by TGF-β. Because TGF-β has been detected in the synovia of patients with rheumatoid arthritis and has been shown to reduce the collagenase levels and proliferation of synovial fibroblast-like cells, it has been proposed by others to be involved beneficially in the reparative processes occurring in arthritic lesions. However, on the basis of our findings, we propose alternative functions for this cytokine-namely, roles in the destructive events as well as in the synovial hyperplasia observed in rheumatoid joints.