The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis

Background: The Fas ligand/Fas receptor (FasL/Fas) system is an important m ediator of apoptosis in the immune system where the juxtaposition of cells expressing the cell-surface ligand induces the apoptotic pathway in Fas-exp ressing lymphocytes. The FasL/Fas system has also been shown to be involved in apoptosis in epithelial tissues, including the involuting rodent prosta te. FasL can be shed through the action of an hitherto unidentified metallo proteinase to yield soluble FasL (sFasL), although the biological activity of sFasL has been disputed. Results: Here we report that the matrix metalloproteinase matrilysin can pr ocess recombinant and cell-associated Past to sFasL, and that matrilysin-ge nerated sFasL was effective at inducing apoptosis in a target epithelial ce ll population. In the involuting mouse prostate, FasL and matrilysin coloca lized to the cell surface in a restricted population of epithelial cells. M ice deficient in matrilysin demonstrated a 67% reduction in the apoptotic i ndex in the involuting prostate compared with wild-type animals, implicatin g matrilysin in this FasL-mediated process. Conclusions: These results show that a functional form of sFasL was generat ed by the action of the metalloproteinase matrilysin, and suggest that matr ilysin cleavage of FasL is an important mediator of epithelial cell apoptos is. (C) 1999 Elsevier Science Ltd. All rights reserved.