Expression and structural analysis of a novel highly inducible gene encoding alpha 1-antitrypsin in rabbit

alpha 1-Antitrypsin is a major plasma proteinase inhibitor whose primary function is to control the proteolytic activity of neutrophil elastase that hydrolyzes structural proteins. This protein, in rabbit is expressed as three isoforms designated as F, S-1, and S-2. An inducible form of this protein has been cloned from an acute-phase cDNA library of rabbit liver. Structural study has revealed that the cloned cDNA is the S-2 isoform previously identified by partial peptide sequence analysis. The amino acid sequence of the reactive center of the S-2 form is not conserved and thus can be categorized as of unorthodox type. mRNA analysis has indicated that the transcription of the S-2 isoform which is normally present at a very low concentration increases more than 100-fold under inflammatory conditions while the expression of the F and S-1 isoforms changes about 1.5-fold under similar conditions. The S-2 isoform is biologically active and capable of inhibiting both elastase and chymotrypsin. The high level of induction of this active isoform of alpha 1-antitrypsin under inflammatory conditions and its apparent resistance to oxidation-mediated inactivation, common to the orthodox forms of alpha 1-antitrypsin, make the S-2 isoform suitable for gene therapy in diseases associated with alpha 1-antitrypsin deficiency.