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Blood, 15 July 2002, Vol. 100, No. 2, pp. 647-653
NEOPLASIA
Response of hairy cells to IFN- involves induction of
apoptosis through autocrine TNF- and protection by adhesion
Peter K. Baker,
Andrew R. Pettitt,
Joseph R. Slupsky,
Hai J. Chen,
Mark A. Glenn,
Mirko Zuzel, and
John C. Cawley
From the Department of Haematology, University of
Liverpool, United Kingdom.
Although hairy cell leukemia is uniquely sensitive to
interferon- (IFN-), the biologic basis for this phenomenon
remains unclear. Here we examine the effects of IFN- on cultured
hairy cells (HCs), taking into account the possible modifying influence of cell adhesion. We make the novel observation that therapeutic concentrations of IFN- kill nonadherent HCs by inducing apoptosis. In keeping with the persistence of HCs in tissues during therapy, such
killing was inhibited by integrin-mediated adhesion to vitronectin or
fibronectin. Exposure of HCs to IFN- resulted in a marked increase
in tumor necrosis factor- (TNF-) secretion. Furthermore, blocking
antibodies to TNF-RI or TNF-RII protected HCs from
IFN--induced apoptosis, demonstrating that such killing
was mediated by TNF-. In the absence of IFN-, exogenous TNF-
did not induce HC apoptosis, showing that IFN- sensitized HCs to the
proapoptotic effect of autocrine TNF-. This sensitization to
TNF--induced killing was attributable to suppression of IAP
(inhibitors of apoptosis) production known to be regulated by the
cytoprotective nuclear factor- B-dependent arm of TNF-
signaling. Moreover, engagement of the receptors for fibronectin or
vitronectin prevented this IFN--induced down-regulation of
IAPs. Understanding of the signals involved in the combined effects of
IFN- and TNF- and abrogation of those induced by integrin
engagement offers the possibility of sensitizing other malignant cells
to IFN--induced killing and thereby extending the therapeutic
use of this cytokine.
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