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J. Exp. Med.,
Volume 187, Number 8, April 20, 1998 1205-1213
By
From the * Institute of Biochemistry, University of Lausanne, BIL Research Centre, CH-1066
Epalinges, Switzerland; and Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)- Clinical Immunology, Department of Internal Medicine, University
Hospital, CH-8044 Zürich, Switzerland
undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-) which, in the case of sFasL, is thought to be implicated in diseases such as hepatitis and AIDS. Here we show that the processing of sFasL
occurs between Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed
sFasL was reduced by >1,000-fold compared with membrane-bound FasL, and injection of
high doses of recombinant sFasL in mice did not induce liver failure. However, soluble FasL
retained its capacity to interact with Fas, and restoration of its cytotoxic activity was achieved
both in vitro and in vivo with the addition of cross-linking antibodies. Similarly, the marginal
apoptotic activity of recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL),
another member of the TNF ligand family, was greatly increased upon cross-linking. These results indicate that the mere trimerization of the Fas and TRAIL receptors may not be sufficient
to trigger death signals. Thus, the observation that sFasL is less cytotoxic than membrane-bound FasL may explain why in certain types of cancer, systemic tissue damage is not detected,
even though the levels of circulating sFasL are high.
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