Current Biology
Volume 9, Issue 24, 30 December 1999, Pages 1441-1447
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Research Papers
The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis

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Abstract

Background: The Fas ligand/Fas receptor (FasL/Fas) system is an important mediator of apoptosis in the immune system where the juxtaposition of cells expressing the cell-surface ligand induces the apoptotic pathway in Fas-expressing lymphocytes. The FasL/Fas system has also been shown to be involved in apoptosis in epithelial tissues, including the involuting rodent prostate. FasL can be shed through the action of an hitherto unidentified metalloproteinase to yield soluble FasL (sFasL), although the biological activity of sFasL has been disputed.

Results: Here we report that the matrix metalloproteinase matrilysin can process recombinant and cell-associated FasL to sFasL, and that matrilysin-generated sFasL was effective at inducing apoptosis in a target epithelial cell population. In the involuting mouse prostate, FasL and matrilysin colocalized to the cell surface in a restricted population of epithelial cells. Mice deficient in matrilysin demonstrated a 67% reduction in the apoptotic index in the involuting prostate compared with wild-type animals, implicating matrilysin in this FasL-mediated process.

Conclusions:The results show that a functional form of sFasL was generated by the action of the metalloproteinase matrilysin, and suggest that matrilysin cleavage of FasL is an important mediator of epithelial cell apoptosis.

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WC Powell, B Fingleton, CL Wilson and LM Matrisian, Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, USA.

M Boothby, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, USA.

Present address for WC Powell: Department of Pathology, USC School of Medicine, Los Angeles, California 90033, USA.

Present address for CL Wilson: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110-1092, USA.

E-mail address for LM Matrisian (corresponding author): [email protected].

WC Powell and B Fingleton contributed equally to this work.