HUMAN NEUTROPHIL ELASTASE DEGRADES INTER-ALPHA-TRYPSIN INHIBITOR TO LIBERATE URINARY TRYPSIN-INHIBITOR RELATED PROTEINS

Urinary trypsin inhibitor (UTI) is a physiological protease inhibitor and inter-alpha-trypsin inhibitor (ITI) is regarded as a precursor of UTI. The purpose of this study is to determine the mechanism of the UT I release from ITI. To examine this, ITI was digested by human neutrop hil elastase at various concentrations, and UTI-related proteins which were of the same size as UTI were obtained. The amino acid sequence o f the 15 amino acid residues at the N-terminal of UTI-related proteins , corresponded to that of UTI. The amino acid sequences of the small a mount of peptides detected corresponded to those of peptides from the heavy chain1 (H1) and the heavy chain2 (H2) of ITI, suggesting that mo st UTI-related proteins do not combine with peptides from the H1 and H 2 of ITI. It was also revealed that UTI-related proteins have several physiological activities similar to those of UTI, i.e., human trypsin inhibitory activity, human neutrophil elastase inhibitory activity, in hibition of tumor necrosis factor-a (TNF-a) production from rat macrop hages and of superoxide production from rabbit leukocytes. These resul ts demonstrated that ITI is a precursor of UTI which is digested by hu man neutrophil elastase to release UTI, and that its elastase inhibito ry activity is derived from UTI.