The activation of synovial mast cells: modulation of histamine release by tryptase and chymase and their inhibitors

Mast cells have been implicated as having pivotal roles in arthritis, but l ittle is known of the processes leading to the activation of synovial mast cells or their potential for pharmacological control. We have investigated the ability of tryptase and chymase, and inhibitors of these major mast cel l proteases to modulate the activation of mast cells from human synovial ti ssue. The tryptase inhibitor drug N-(1-hydroxy-2-naphthoyl)-L-arginyI-L-pro linamide hydrochloride (APC366) inhibited immunoglobulin E (IgE)-dependent histamine release in a dose-dependent manner, with about 70% inhibition bei ng achieved at a dose of 300 muM. Histamine release stimulated by calcium i onophore A23187 was also inhibited by this compound. The chymase inhibitor chymostatin inhibited IgE-dependent histamine release by approximately 60% at 1 mug/ml. Tryptase at concentrations of 3.0 mug/ml and greater stimulate d histamine release from synovial cells, which was dependent on catalytic a ctivity, whereas chymase had little effect on these cells. The activation o f mast cells by tryptase may represent an amplification process in the syno vium. The mast cell stabilising properties of inhibitors of tryptase and ch ymase could be of therapeutic value in arthritis. (C) 2001 Elsevier Science B.V. All rights reserved.