Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor

A number of serine proteases, matrix metalloproteases, and cysteine proteas es were evaluated for their ability to cleave and inactivate the antiprotea se, secretory leueoprotease inhibitor (SLPI). None of the serine proteases or the matrix metalloproteases examined cleaved the SLPI protein. However, incubation with cathepsins B, L, and S resulted in the cleavage and inactiv ation of SLPI. All three cathepsins initially cleaved SLPI between residues Thr(67) and Tyr(68). The proteolytic cleavage of SLPI by all three catheps ins resulted in the loss of the active site of SLPI and the inactivation of SLPI anti-neutrophil elastase capacity. Cleavage and inactivation were cat alytic with respect to the cathepsins, so that the majority of a 400-fold e xcess of SLPI was inactivated within 15 min by cathepsins L and S. Analysis of epithelial lining fluid samples from individuals with emphysema indicat ed the presence of cleaved SLPI in these samples whereas only intact SLPI w as observed in control epithelial lining fluid samples. Active cathepsin L was shown to be present in emphysema epithelial lining fluid and inhibition of this protease prevented the cleavage of recombinant SLPI added to emphy sema epithelial lining fluid. Taken together with previous data that demons trates that cathepsin L inactivates alpha (1)-antitrypsin, these findings i ndicate the involvement of cathepsins in the diminution of the lung antipro tease screen possibly leading to lung destruction in emphysema.