Mast-cell proteases

Chymase (mast cell protease type II), a chymotrypsin-like protease, is a serine protease found in mucosal mast cells, which catalyzes the conversion of angiotensin I to angiotensin II and of big endothelin 1 (ET1) to ET1 (1-31). 

Mast cell protease A3 is less well characterized than tryptase and chymase in terms of physiological substrates. It is involved, among its other functions, in angiotensin metabolism. 

Several of the postulated roles for nematode-secreted AChEs assume that they gain access to the intestinal mucosa. Several possibilities exist for transport of parasite AChE across the epithelial cell barrier, such as (i) utilization of existing pathways for receptor-mediated transcytosis (ii) a paracellular route facilitated by parasite-secreted proteases as observed for a bacterial elastase (Azghani et al., 1993) and (iii) increased paracellular permeability resulting from inflammatory events in the mucosa. We consider the latter suggestion most likely, as this has been duplicated by ex vivo perfusion with rat mast cell protease II (Scudamore et al., 1995). Moreover, cholinergic stimulation attenuates epithelial barrier properties to macromolecules in rat ileal crypts (Phillips et al., 1987). 

Scudamore, C.L., Thornton, E.M., McMillan, L., Newlands, G.F.J. and Miller, H.R.P. (1995) Release of the mucosal mast cell granule chymase, rat mast cell protease-II, during anaphylaxis is associated with the rapid development of paracellular permeability to macromolecules in rat jejunum. Journal of Experimental Medicine 182, 1871—1881. 

The mechanisms whereby mast cells enhance host protection to H. polygyms and T. spiralis (and whether these are related to the leak-lesion hypothesis) have not yet been fully defined. Certainly, mast cells contribute to intestinal inflammation during infection through the secretion of a range of cytokines (Gordon et al., 1990) and vasoactive substances (see above). In addition, the release of mast cell proteases are known to increase enterocyte permeability to macromolecules in the rat intestine (Scudamore et al., 1995) and regulate epithelial cell functions at other mucosal sites (Cairns and Walls, 1996). 

Eklund, RK., Ghildyal, N., Austen, K.F. and Stevens, R.L. (1993) Induction by IL-9 and suppression by IL-3 and IL-4 of the levels of chromosome 14-derived transcripts that encode late expressed mouse mast cell proteases Journal of Immunology 151, 4266 273. 

This enzyme [EC 3.4.21.39], also referred to as mast cell protease I and skeletal muscle (SK) protease, is an endopeptidase that has been isolated from mast cell granules. It belongs to the peptidase family SI and catalyzes the hydrolysis of peptide bonds, preferring Phe-Xaa > Tyr-Xaa > Trp-Xaa > Leu-Xaa. 

Complement components—Clr, Cl and C2 Complement factors—B, D and I Cytotoxic cell proteases—granzymes A to H Mast cell proteases—... 

LPL M-CSFR MHC MHC-II MMCP MMP NG2 PDGF PPAR RANK Sca-1 SM22 L lipoprotein monocyte - colony stimulation factor receptor myosin heavy chain MHC class II mouse mast cell protease metalloproteinase proteoglycan heparan-sulfate related to pericytes activity platelet-derived growth factor peroxisome proliferator-activated receptor gamma receptor activator of NF-kappa 3 stem cell antigen 1 smooth cell protein structurally related to calponin, both actin and tropomyosin ligands... 

One goal in the design of an inhibitor is specificity. Often this is a considerable challenge since physiological systems contain a number of closely related proteases. For example, there are at least four chymo-trypsin-like enzymes in humans. These include pancreatic chymotrypsin, cathepsin G, and two mast cell proteases (the human enzymes have not been characterized yet, but two are found in rats). All of these enzymes... 

Suc-Pro-Leu-PheCH2Cl mast cell protease I (rat) ° mast cell protease II (rat) ° cathepsin G... 

Goldstein, S.M., Leong, J. and Bunnett, N.W. (1991). Human mast cell proteases hydrolyze neurotensin, kinetensin and Leu5-enkephalin. Peptides 12, 995-1000. 

Goldstein, S.M., Leong, J., Schwartz, L.B. and Cooke, D. (1992). Protease composition of exocytosed human skin mast cell protease-proteoglycan complexes tryptase resides in a complex distinct from chymase and carboxypeptidase. J. Immunol. 148, 2475-2482. 

King, S.J., Miller, H.R., Newlands, G.F. and Woodbury, R.G. (1985). Depletion of mucosal mast cell protease by gluco-corticosteroids effect on intestinal anaphylaxis in the rat. Proc. Natl. Acad. Sci. USA 82, 1214-1218. 

K., Neurath, H. and Woodbury, RG. (1985). Mammalian chymotrypsin-like enzymes. Comparative reactivities of rat mast cell proteases, human and dc skin proteases and human cathepsin G with peptide-4-nitroanilide substrates and with peptide chloromethyl ketone and sulphonyl fluoride inhibitors. Biochemistry 24, 2048-2058. 

Human skin chymotryptic proteinase isolation and relation to cathepsin G and rat mast cell protease. J. Biol. Chem. 258, 2973-2978. 

G.H. Caughey, Mast Cell Proteases in Immunology and Biology, Marcel Dekker, New York, 1995. 

Caughey GH (1995) Mast cell proteases in immunology and biology. Marcel-Decker, New-York, p 305... 

MacQueen G, Marshall J, Perdue M, Siegel S, Bienenstock J. Pavlonian conditioning of rat mucosal mast cells to secrete rat mast cell protease II. Science 1989 ... 

Neutrophil and mast cell proteases are important in initiating ey tokine and mediator release from epithelium (62,63) and in modulating epithelial permeability (77). Similarly, proteases from inflammatory eells, sueh as eosinophils, as well as Irom elsewhere within the lung may also be important in respiratory disease... 

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