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 little 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 cell proteases to modulate the activation of mast cells from human synovial tissue. The tryptase inhibitor drug N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide hydrochloride (APC366) inhibited immunoglobulin E (IgE)-dependent histamine release in a dose-dependent manner, with about 70% inhibition being achieved at a dose of 300 microM. Histamine release stimulated by calcium ionophore A23187 was also inhibited by this compound. The chymase inhibitor chymostatin inhibited IgE-dependent histamine release by approximately 60% at 1 microg/ml. Tryptase at concentrations of 3.0 microg/ml and greater stimulated histamine release from synovial cells, which was dependent on catalytic activity, whereas chymase had little effect on these cells. The activation of mast cells by tryptase may represent an amplification process in the synovium. The mast cell stabilising properties of inhibitors of tryptase and chymase could be of therapeutic value in arthritis.
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Immunopharmacology Group, University of Southampton, South Block, Southampton General Hospital, Mailpoint 837, SO16 6YD, Southampton, UK.
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Walls
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D000001:Calcimycin / Q000494:pharmacology; D053818:Chymases; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006636:Histamine Release / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism; D053802:Tryptases
D004151:Dipeptides; D018836:Inflammation Mediators; D007476:Ionophores; C094700:N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D007073:Immunoglobulin E; D000001:Calcimycin; C002101:chymostatin; D012697:Serine Endopeptidases; D053818:Chymases; D053802:Tryptases