Proteolytic inactivation of human α1 antitrypsin by human stromelysin

Abstract

α₁Antitrypsin (α₁AT) is the main physiological inhibitor of neutrophil elastase, a serine protease which has been implicated in tissue degradation at inflammatory sites. We report here that the connective tissue metalloproteinase, stromelysin, cleaved α₁AT (54 kDa), producing fragments of approximately 50 kDa and 4 kDa, as shown by gel electrophoresis. The cleavage of α₁AT was accompanied by inactivation of its elastase inhibitory capacity. Isolation of the 4 kDa fragment by reversed‐phase HPLC, followed by N‐terminal amino acid sequencing, demonstrated that the cleavage of α₁AT occurred at the Pro³⁵⁷‐Met³⁵⁸ (P₂–P₁) peptide bond, one peptide bond to the N‐terminal side of the inhibitory site. We suggest that stromelysin may potentiate the activity of neutrophil elastase by proteolytically inactivating α₁AT.