REGULATION OF C1 INHIBITOR SYNTHESIS

The primary biologic roles of C1 inhibitor (C1-INH) are the regulation of activation of the classical complement pathway and of the contact system of kinin formation. Heterozygosity for deficiency or dysfunctio n of C1-INH results in hereditary angioedema (HAE). This deficiency re sults in loss of homeostasis with unregulated complement and contact s ystem activation. Due to the consequent C1-INH consumption, plasma lev els of C1-INH in patients with HAE are decreased below 50% of normal. In addition, diminished synthesis contributes to the lowered levels in some patients. The hepatocyte is the primary source of C1-INH, althou gh a number elf other cell types, including peripheral blood monocytes , microglial cells, fibroblasts, endothelial cells, the placenta, and megakaryocytes also synthesize and secrete the protein both in vivo an d in vitro. Interferon-gamma and a (IFN), colony stimulating factor-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) all induce C1-INH synthesis in a variety of cell types. The IFN-response e lements in the 5'-flanking region and in the first intron have been pa rtially characterized, as have several of the promoter elements that d irect basal transcription of the gene.:However, although androgen ther apy, in vivo, results in an increase in C1-INH plasma levels, a direct effect of androgens on C1-INH synthesis has not been convincingly dem onstrated. Although the C1-INH gene contains a potential glucocorticoi d/androgen response element, this element does not appear to respond t o androgen. Continued analysis of the transcriptional regulation of th e C1-INH gene may lead to new approaches to therapy of HAE.