Blood, 1 May 2001, Vol. 97, No. 9, pp. 2791-2797
NEOPLASIA
Autocrine cell suicide in a Burkitt lymphoma cell line
(Daudi) induced by interferon 
: involvement of tumor necrosis
factor as ligand for the CD95 receptor
Heinz Gisslinger,
Razelle Kurzrock,
Bettina Gisslinger,
Shuwei Jiang,
Shuren Li,
Irene Virgolini,
Wolfgang Woloszczuk,
Michael Andreeff, and
Moshe Talpaz
From the Departments of Internal Medicine I and Nuclear
Medicine and the Ludwig Boltzmann Institut for Experimental
Endocrinology, University of Vienna, Austria; and the M.D. Anderson
Cancer Center, University of Texas, Houston.
The CD95 receptor, a member of the tumor necrosis factor
(TNF) receptor superfamily, mediates signals for cell death on specific ligand or antibody engagement. It was hypothesized that interferon 
(IFN-) induces apoptosis through activation of the CD95-mediated pathway and that CD95 and ligands of the death domain may belong to the
group of IFN-stimulated genes. Therefore, the effect of IFN- on
CD95-CD95L expression, on the release of TNF-, and on TNF receptor 1 expression in an IFN-sensitive human Burkitt lymphoma cell line (Daudi)
was investigated. After 5 days' incubation, apoptosis in 81% of
IFN--treated Daudi cells was preceded by a release of TNF- and
an induction of CD95 receptor expression. Although supernatants of
IFN-treated Daudi cells induced apoptosis of CD95-sensitive Jurkat
cells, CD95L was undetectable on protein or on messenger RNA levels,
and the weak initial expression of TNF receptor 1 increased only
slightly during IFN treatment. Surprisingly, binding of
TNF- to CD95 was observed and confirmed by 3 different techniques
enzyme-linked immunosorbent assay using immobilized CD95:Fc-immunoglobulin G, immunoprecipitation assay using CD95 receptor precipitates of Daudi cells, and binding of sodium iodide 125-TNF- to Daudi cells, which was strongly stimulated by IFN- and inhibited by CD95L, CD95:Fc, unlabeled TNF-, and anti-TNF- antibody. Preincubation of Daudi cells with antagonists of the CD95-mediated pathway resulted in an inhibition of IFN--mediated cell death. The present investigation shows that IFN- induces autocrine cell suicide of Daudi cells by a cross-talk between the CD95
receptor and TNF-. The CD95 receptor can be considered a third TNF
receptor, in addition to p55 and p75.
