Abstract
There has long been evidence that inhibitors of chymotryptic proteinases can inhibit the degranulation of rodent mast cells, but their actions on human mast cells and the contribution of mast cell chymase itself have received little attention. We investigated the ability of the selective chymase inhibitor Z-Ile-Glu-Pro-Phe-CO2Me and other proteinase inhibitors to inhibit chymase and cathepsin G activity, and we examined their potential to modulate the responsiveness of mast cells dispersed from human skin, lung, and tonsil tissues. IgE-dependent histamine release from skin mast cells was inhibited by up to about 80% after preincubation with Z-Ile-Glu-Pro-Phe- CO2Me (up to 0.1 μM), 70% with chymostatin (17 μM), and 60% with soybean trypsin inhibitor (0.5 μM). The mast cell-stabilizing properties of chymase inhibitors appeared to be greater for skin mast cells than for those from lung, whereas tonsil mast cells were relatively unresponsive. There were marked differences in the time course of responses to inhibitors, and the effect was dependent on the stimulus, with calcium ionophore-induced histamine release being unaffected. Incubation of dispersed skin, lung, or tonsil cells for up to 45 min with purified chymase failed to induce histamine release, although preincubation of cells with chymase was able to suppress IgE-dependent activation. Chymase could thus contribute to mast cell degranulation and after secretion could provide a feedback mechanism to limit this process. Nevertheless, inhibitors of chymase can be potent mast cell stabilizers, particularly in the skin.
Footnotes
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Send reprint requests to: Dr. Andrew F. Walls, Immunopharmacology Group, South Block (Mail Point 837), Southampton General Hospital, Southampton SO16 6YD, United Kingdom. E-mail:afw1{at}soton.ac.uk
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↵1 This work was supported by grants from the Medical Research Council and the Wessex Medical Trust, UK.
- Abbreviations:
- AAPF-S-Bzl
- N-succinyl-l-Ala-l-Ala-l-Pro-l-Phe-thiobenzyl ester
- HBSS
- HEPES-buffered salt solution
- AAPFpNA
- N-succinyl-l-Ala-l-Ala-l-Pro-l-Phe-p-nitroanilide
- BAPNA
- N-benzoyl-dl-arginine-p-nitroanilide
- NA
- nitroanilide
- MCTC
- mast cell subset containing tryptase and chymase
- MCT
- mast cell subset containing tryptase but not chymase
- SBTI
- soybean trypsin inhibitor
- ZIGPFM
- Z-Ile-Glu-Pro-Phe-CO2Me
- Received February 9, 1999.
- Accepted July 13, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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