Abstract:
:Although hairy cell leukemia is uniquely sensitive to interferon-alpha (IFN-alpha), the biologic basis for this phenomenon remains unclear. Here we examine the effects of IFN-alpha 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-alpha 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-alpha resulted in a marked increase in tumor necrosis factor-alpha (TNF-alpha) secretion. Furthermore, blocking antibodies to TNF-RI or TNF-RII protected HCs from IFN-alpha-induced apoptosis, demonstrating that such killing was mediated by TNF-alpha. In the absence of IFN-alpha, exogenous TNF-alpha did not induce HC apoptosis, showing that IFN-alpha sensitized HCs to the proapoptotic effect of autocrine TNF-alpha. This sensitization to TNF-alpha-induced killing was attributable to suppression of IAP (inhibitors of apoptosis) production known to be regulated by the cytoprotective nuclear factor-kappaB-dependent arm of TNF-alpha signaling. Moreover, engagement of the receptors for fibronectin or vitronectin prevented this IFN-alpha-induced down-regulation of IAPs. Understanding of the signals involved in the combined effects of IFN-alpha and TNF-alpha and abrogation of those induced by integrin engagement offers the possibility of sensitizing other malignant cells to IFN-alpha-induced killing and thereby extending the therapeutic use of this cytokine.
journal_name
Bloodjournal_title
Bloodauthors
Baker PK,Pettitt AR,Slupsky JR,Chen HJ,Glenn MA,Zuzel M,Cawley JCdoi
10.1182/blood.v100.2.647subject
Has Abstractpub_date
2002-07-15 00:00:00pages
647-53issue
2eissn
0006-4971issn
1528-0020journal_volume
100pub_type
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