Inhibition of plasma kallikrein by Cl-inhibitor: role of endothelial cells and the amino-terminal domain of Cl-inhibitor

Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with CI-inhibitor deficiency. Heterozygous individuals with <50% levels of active CI-inhibitor are susceptible to angioedema attacks indicating a critical need for CI-inhibitor to be present at maximum levels to prevent unwanted prekallikrein activation. Studies with purified proteins do not adequately explain this observation. Therefore to investigate why reduction of CI-inhibitor to levels seen in angioedema patients results in excessive kallikrein generation we examined the effect of endothelial cells on the inhibition of kallikrein by CI-inhibitor. Surprisingly, it was found that a CI-inhibitor concentration of greater than 1 muM was needed to inhibit 3 nM kallikrein. We propose that this apparent protection from inhibition was mediated by kallikrein binding to the cells via the heavy chain in a high molecular weight kininogen and zinc independent manner. Protection of kallikrein from inhibition was not observed when CI-inhibitor truncated in the amino-terminal domain by the StcE metalloproteinase was used, which suggests a novel function for this unique domain. The requirement for high concentrations of CI-inhibitor to fully inhibit kallikrein is consistent with the fact that reduced levels of CI-inhibitor result in the kallikrein activation seen in angioedema.