Neutrophil proteases

C5a is inactivated by the myeloperoxidase-H202 system, which oxidises a methionine residue (Met 70) on the molecule group A streptococcal endo-proteinases also abolish chemotactic activity of C5a and related compounds. Neutrophil lysosomal enzymes (e.g. elastase and cathepsin G) also destroy C5a chemotactic activity, but as these proteases are inhibited by the serum antiproteinases, a -antiproteinase and a2-macroglobulin, the physiological role of neutrophilic proteases in the inactivation of C5a is questionable. Two chemotactic factor inactivators have been found in human serum an a-globulin that specifically and irreversibly inactivates C5-derived chemotactic factors, and a / -globulin that inactivates bacterial chemotactic factors. These activities are heat labile (destroyed by treatment at 56 °C for 30 min) and are distinct from those attributable to anaphylatoxin inactivator. An apparently specific inhibitor of C5-derived chemotactic activity has also been described in human synovial fluid and peritoneal fluid. This factor (molecular mass of 40 kDa) is heat stable and acts directly on C5a. 

Moll T, Dejana E, Vestweber D In vitro degradation of endothelial catenins by a neutrophil protease. J Cell Biol 1998 140 403 07. 

J. P. Levesque, Y. Takamatsu, S. K. Nilsson, D. N. Haylock, and P. J. Simmons, Vascular cell adhesion molecule-1 (CD 106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood, 98 (2001) 1289-1297. 

Ual adherens junctions. Combined immunofluorescence and biochemical data suggested that following adhesion of polymorphonuclear leucocytes to the endothelial cell surface, P-catenin as well as pla-koglobin was lost from the cadherin/catenin complex and from total cell lysates (Del Maschio et al. 1996, Allport etal. 1997). However, Moll etal. (1998) demonstrated that the adhesion-dependent disappearance of endotheUal catenins in these experiments was not mediated by a leucocyte to en-dotheUum signalhng event, but was due to the activity of a neutrophil protease which had been experimentally released upon lysis and handUng of the co-incubated neutrophils and endotheUal ceUs. 

Additional serine proteases have been found in chronic wounds and neutrophils probably are also the primary source of these enzymes. These include cathepsin G, another cationic serine protease with broad substrate specificity, urokinase-type plasminogen activator (itfA), and protease 3 (3,32-35). In all probability, when looked for, elevated levels of additional neutrophil proteases will be found in chronic dermal ulcers. 

Figure 4, Schematic of interactions of neutrophil enzymatic and oxidative products and endogenous protease inhibitors. Short-lived and long-lived oxidants generated by the neutrophil NADPH oxidase/myeloperoxidase system can activate latent proteases (MMP-S and MMP-9) as well as inactivate major protease inhibitors such as TIMP, armacroglobulin, and aj-protease inhibitor. Furthermore, neutrophil proteases can also interact in a synergistic fashion as evidenced by the ability of MMP-8 to degrade aj-protease inhibitor and elastase to degrade TIMP.

One intensively investigated feature of the inflammatory process in COPD is the release of proteases from neutrophils and monocytic cells that destroy elastin and other components of the interstitial matrix (Table 1). The best studied protease is neutrophil elastase. Independent of its elastolytic activity, neutrophil elastase is a potent secretagogue. More recently matrix metalloproteases (MMP) have received increasing attention, in particular MMP 12 (macrophages elastase). To which extent and how exactly these proteases become activated is not clear at present. 

Pham CT (2006) Neutrophil serine proteases specific regulators of inflammation. Nat Rev Immunol 6 541-550... 

Proudfoot AE, Buser R, Borlat F et al (1999) Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors. J Biol Chem 274 32478-32485 Qin AP, Zhang HE, Qin ZH (2008) Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neurosci Bull 24 117-123 Richter R, Bistrian R, Escher S et al (2005) Quantum proteolytic activation of chemokine CCL15 by neutrophil granulocytes modulates mononuclear cell adhesiveness. J Immunol 175 1599-1608... 

Hermant B, Bibert S, Concord E, et al. Identification of proteases involved in the proteolysis of vascular endothelium cadherin during neutrophil transmigration. J Biol Chem 2003 278(16) 14002-14012. 

The protective antiprotease -antitrypsin (AAT) inhibits several protease enzymes, including neutrophil elastase. In the presence of unopposed AAT activity, elastase attacks elastin, which is a major component of alveolar walls. A hereditary deficiency of AAT results in an increased risk for premature development of emphysema. In the inherited disease, there is an absolute deficiency of AAT. In emphysema resulting from cigarettesmoking, the imbalance is associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several other proteases, including cathepsins and metalloproteinases. In addition, oxidative stress reduces antiprotease (or protective) activity. 

Almeida, R. P., Melchior, M., Campanelli, D., Nathan, C., Gabay, J. E. (1991). Complementary DNA sequence of human neutrophil azurocidin, an antibiotic with extensive homology to serine proteases. Biochem. Biophys. Res. Commun. 177, 688-95. 

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