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Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2329-2336
Interferon- -induced membrane PAF-receptor expression
confers tumor cell susceptibility to NK perforin-dependent lysis
Christian Berthou,
Jean-François Bourge,
Yuehe Zhang,
Annie Soulié,
Daniela Geromin,
Yves Denizot,
François Sigaux, and
Marilyne Sasportes
From INSERM U462, Hôpital St Louis, Paris, France; and EP CNRS
1I8 Faculté de Médicine, Limoges, France.
Perforin is known to display a membranolytic activity on tumor
cells. Nevertheless, perforin release during natural killer (NK)-cell
activation is not sufficient to induce membrane target-cell damage. On
the basis of the ability of perforin to interact with phospholipids
containing a choline phosphate headgroup, we identify the
platelet-activating factor (PAF) and its membrane receptor as crucial
components in tumor cell killing activity of human resting NK cells. We
demonstrate for the first time that upon activation, naive NK cells
release the choline phosphate-containing lysolipid PAF, which binds to
perforin and acts as an agonist on perforin-induced membrane damage.
PAF is known to incorporate cell membranes using a specific receptor.
Here we show that interferon- (IFN-) secreted from activated NK
cells ends in PAF-receptor expression on perforin-sensitive K562 cells
but not on perforin-resistant Daudi cells. In order to prove the
capacity of PAF to interact simultaneously with its membrane PAF
receptor and with perforin, we successfully co-purified the 3 components in the presence of bridging PAF molecules. The functional
activity of this complex was further examined. The aim was to determine
whether membrane PAF-receptor expression on tumor cells, driven to
express this receptor, could render them sensitive to the perforin
lytic pathway. The results confirmed that transfection of the
PAF-receptor complementary DNA into major histocompatibility complex
class I and Fas-receptor negative tumor cells restored susceptibility
to naive NK cells and perforin attack. Failure of IFN- to induce
membrane PAF receptor constitutes the first described mechanism for
tumor cells to resist the perforin lytic pathway.
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