Serine proteases and their congeners

Human PMN granules contain several neutral proteases, and congeners that manifest microbicidal activity in vitro. The most prominent of these are cathepsin G (a chymotrypsin-like enzyme), elastase and an enzymatically-inactive elastase congener, 'azurocidin'. It has been suggested that translocation of serine proteases to the external surface of activated neutrophils, where they are unaffected by protease inhibitors, may facilitate chemotaxis and their ability to exit the vascular compartment and enter sites of inflammation. Neutrophils of patients with Chédiak-Higashi syndrome contain greatly reduced amounts of both cathepsin G and elastase, deficiencies that may contribute to their impaired bactericidal performance in vitro and to the frequent infections sustained by these patients in vivo.

Cathepsin G is a 27 kDa, variably glycosylated cationic protein that is found in the azurophil granules of human PMNs. It also occurs, but in much smaller amounts, in human blood monocytes. The five exon cathepsin G gene is located on chromosome 14, adjacent to the genes for lymphocyte granzymes B and H and mast cell chymase 1. Cathepsin G kills gram-positive and gram-negative bacteria as well as certain fungi, and is especially effective against Neisseria gonorrhoeae. The bactericidal activity of purified cathepsin G is inhibited by increasing ionic strength or serum concentration. Enzymatically-inactive cathepsin G retains bactericidal and fungicidal activity.

The human neutrophil elastase gene also has five exons, but is located on the short arm of chromosome 19, extremely close to genes for azurocidin, proteinase 3 and granzymes A, B, H and M. Human neutrophil elastase exists as a mixture of four isoenzymes that differ only in their carbohydrate content. Elastase can degrade bacterial cell wall protein, potentiate the bacteriolytic activity of lysozyme, and potentiate the microbicidal activity of cathepsin G in vitro by a nonenzymatic mechanism. Theoretically, it might also cleave the antimicrobial 25 kDa N-terminal portion of BPI from the intact holoprotein molecule and participate in trimming the cathelin domain from hCAP-18/FALL-39 to generate the antimicrobial peptide it carries. Weak intrinsic antibacterial activity of elastase has been demonstrated towards the gram-negative bacterium Acinetobacter 199 A, but detailed studies with other bacteria have not been reported.

Azurocidin (also called CAP-37) is a 29 kDa protein that shares considerable N-terminal sequence homology with the human neutrophil's elastase and cathepsin G. Because it contains glycine instead of serine at the expected catalytic site, azurocidin lacks protease and peptidase activity and does not bind [3H]di-isopropyl fluorophosphate. Purified azurocidin kills £. coli, Streptococcus faecalis and C. albicans in vitro, showing optimal activity under acidic conditions (pH5.5) in low ionic strength media. It displays considerable activity against deep rough mutants of S. typhimurium and, at 5 pg ml"1, is also active against many other gram-negative bacteria, although Proteus mirabilis, Proteus vulgaris and Serratia marcescens are relatively resistant. Like defensins, azurocidin is a chemoattractant for T lymphocytes and monocytes. Autoantibodies to azurocidin (and other neutrophil granule proteins) are found in some patients with vasculitis.

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