C1-inhibitor-serine proteinase complexes and the biosynthesis of C1- inhibitor by Hep G2 and U 937 cells

The biosynthesis of the serpin α₁-proteinase inhibitor is regulated by a feedback mechanism whereby complexes between α₁-proteinase inhibitor and serine proteinases bind to liver cells and monocytes, a reaction that activates α₁-proteinase-inhibitor gene transcription. Such a mechanism may form the basis for the development of new therapeutic strategies for serpin deficiency states with reduced levels of otherwise normally functioning serpins. This issue was addressed for C1-inhibitor, the missing serpin in hereditary angioedema. C1-inhibitor biosynthesis by Hep G2 hepatoma cells was assessed by enzyme-linked immunosorbent assay, by metabolic labeling followed by immunoprecipitation, and by Northern blotting. C1-inhibitor biosynthesis was stimulated by γ-interferon (100 U/mL) but not by cell exposure to C1- inhibitor-kallikrein (1 μmol/L), C1-inhibitor-C1̄s (1 μmol/L), and C1- inhibitor-plasmin complexes (1 μmol/L) or to reactive site-cleaved C1- inhibitor (1 μmol/L). Moreover, radioiodinated C1̄s-C1-inhibitor complex did not bind to Hep G2 cells. C1-inhibitor-kallikrein complex was also without effect on C1-inhibitor mRNA in U 937 cells. Therefore, the proposed mechanism, by which serpin-enzyme complex or reactive site-cleaved serpin binding to a specific receptor provides a signal for the stimulation of the biosynthesis of that serpin, is not operative for the biosynthesis of C1- inhibitor by Hep G2 or U 937 cells.