Intracellular signal transduction in proliferation of synovial cells.

We investigated some steps in the signal transduction pathway leading to the proliferation of synovial cells. 12-o-tetradecanoyl phorbol-13-acetate (TPA) which is known to stimulate phospholipid- and Ca(2+)-dependent protein kinase (C-kinase) enhanced the proliferation of synovial cells. The proliferation of synovial cells induced by interleukin-1 beta. Tumour necrosis factor alpha and granulocytes/macrophages colony stimulating factor, was inhibited by a potent C-kinase inhibitor, H7. These findings strongly suggested that the signal transduction pathway leading to proliferation of synovial cells is transmitted via C-kinase activation. Prostaglandin E2, which is known to stimulate adenylate cyclase, leading to the elevation of intracellular c-AMP level, inhibited the proliferation of synovial cells. This effect could also be mimicked by the addition of a cell permeable c-AMP analog, dibutyryl c-AMP or theophylline. Studies suggest that the feedback signal for proliferation of synovial cells was transmitted through c-AMP. We therefore conclude that signals for stimulation and inhibition of synovial cell proliferation are transmitted through different pathways.