Response of hairy cells to IFN-alpha involves induction of apoptosis through autocrine TNF-alpha and protection by adhesion.
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.
Baker
Peter K
PK
Department of Haematology, University of Liverpool, United Kingdom. pbaker@liv.ac.uk
Pettitt
Andrew R
AR
Slupsky
Joseph R
JR
Chen
Hai J
HJ
Glenn
Mark A
MA
Zuzel
Mirko
M
Cawley
John C
JC
D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000502:physiology; D016898:Interferon-alpha / Q000494:pharmacology* / Q000502:physiology; D007943:Leukemia, Hairy Cell / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016326:Extracellular Matrix Proteins; D016023:Integrins; D016898:Interferon-alpha