C1-inhibitor-serine proteinase complexes and the biosynthesis of C1-inhibitor by Hep G2 and U 937 cells.
The biosynthesis of the serpin alpha 1-proteinase inhibitor is regulated by a feedback mechanism whereby complexes between alpha 1-proteinase inhibitor and serine proteinases bind to liver cells and monocytes, a reaction that activates alpha 1-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 immunosorbant assay, by metabolic labeling followed by immunoprecipitation, and by Northern blotting. C1-inhibitor biosynthesis was stimulated by gamma-interferon (100 U/mL) but not by cell exposure to C1-inhibitor-kallikrein (1 mumol/L), C1-inhibitor-C1s (1 mumol/L), and C1-inhibitor-plasmin complexes (1 mumol/L) or to reactive site-cleaved C1-inhibitor (1 mumol/L). Moreover, radioiodinated C1s-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.
Patston
P A
PA
Department of Medicine, Vanderbilt University, Nashville, TN 37232.
Medcalf
R L
RL
Kourteva
Y
Y
Schapira
M
M
D000595:Amino Acid Sequence; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005246:Feedback; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D012697:Serine Endopeptidases / Q000502:physiology*; D015843:Serpins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D003174:Complement C1 Inactivator Proteins; D012333:RNA, Messenger; D015843:Serpins; D003907:Dexamethasone; D007371:Interferon-gamma; D012697:Serine Endopeptidases