Regulation of pro-apoptotic leucocyte granule serine proteinases by intracellular serpins

Caspase activation and apoptosis can be initiated by the introduction of se rine proteinases into the cytoplasm of a cell. Cytotoxic lymphocytes have e volved at least one serine proteinase with specific pro-apoptotic activity (granzyme B), as well as the mechanisms to deliver it into a target cell, a nd recent evidence suggests that other leucocyte granule proteinases may al so have the capacity to kill if released into the interior of cells. For ex ample, the monocyte/granulocyte proteinase cathepsin G can activate caspase s in vitro, and will induce apoptosis if its entry into cells is mediated b y a bacterial pore-forming protein. The potent pro-apoptotic activity of gr anzyme B and cathepsin G suggests that cells producing these (or other) pro teinases would be at risk from self-induced death if the systems involved i n packaging, degranulation or targeting fail and allow proteinases to enter the host cell cytoplasm. The purpose of the present review is to describe recent work on a group of intracellular serine proteinase inhibitors (serpi ns) which may function in leucocytes to prevent autolysis induced by the gr anule serine proteinases.