The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1205/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 8, April 20, 1998 1205-1213

Articles

Conversion of Membrane-bound Fas(CD95) Ligand to Its Soluble Form Is Associated with Downregulation of Its Proapoptotic Activity and Loss of Liver Toxicity

Pascal Schneider*, Nils Holler*, Jean-Luc Bodmer*, Michael Hahne*, Karl Frei{ddagger}, Adriano Fontana{ddagger}, and Jürg Tschopp*

From the * Institute of Biochemistry, University of Lausanne, BIL Research Centre, CH-1066 Epalinges, Switzerland; and {ddagger} Clinical Immunology, Department of Internal Medicine, University Hospital, CH-8044 Zürich, Switzerland

Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-{alpha} undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-{alpha}) 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.

Address correspondence to Jürg Tschopp, Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41-21-692-5738; Fax: 41-21-692-5705; E-mail: jurg.tschopp{at}ib.unil.ch

1Abbreviations used in this paper: aa, amino acids; DTAF, dichlorotriazinglaminofluorescein; FADD, Fas-associated death domain–containing protein; Fas/Fc, Fas with human immunoglobulin Fc; h, human; L, ligand; mu, murine; s, soluble; TRAIL, TNF-related apoptosis-inducing ligand; TWEAK, TNF-related ligand that weakly induces apoptosis.


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