Effect of pseudomonas elastase on human mononuclear phagocyte alpha 1-antitrypsin expression.
The net balance of neutrophil elastase and its inhibitor, alpha 1-antitrypsin (alpha 1-AT), is a critical determinant of connective tissue turnover during homeostasis and in disease states. In addition to liver-derived alpha 1-AT, which translocates from blood to tissues, this elastase-alpha 1-AT balance is maintained by expression of alpha 1-AT at the local tissue level in resident mononuclear phagocytes. Our previous studies have shown that this elastase-alpha 1-AT balance is also tightly controlled at a cellular level in that addition of exogenous neutrophil elastase (serpine-type elastase) to cultured mononuclear phagocytes is associated with an increase in expression of the alpha 1-AT gene. Subsequent studies have demonstrated that this novel regulatory loop involves interaction between exogenous neutrophil elastase and endogenous alpha 1-AT inducing a structural rearrangement in the alpha 1-AT molecule and exposing highly conserved conformation-specific domain of alpha 1-AT, which can then be recognized by a specific cell surface receptor, the serpine-enzyme complex receptor. In the following study, we examined the effect of a bacterial metalloelastase, Pseudomonas aeruginosa elastase, on expression of alpha 1-AT in human mononuclear phagocytes. We show that pseudomonas elastase inactivates monocyte-derived alpha 1-AT by limited proteolysis but, in so doing, alpha 1-AT becomes recognized by the serpine-enzyme complex receptor and mediates an increase in de novo synthesis of alpha 1-AT in these cells. However, the concentrations of pseudomonas elastase needed to proteolytically inactivate alpha 1-AT in monocyte culture fluid are higher than those required for inactivation of purified plasma alpha 1-AT.(ABSTRACT TRUNCATED AT 250 WORDS)
Barbey-Morel
C
C
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Perlmutter
D H
DH
D001693:Biological Transport, Active; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism / Q000494:pharmacology*; D011549:Pseudomonas / Q000201:enzymology; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism
D000515:alpha 1-Antitrypsin; D000511:alpha-Macroglobulins; D010196:Pancreatic Elastase