IFN-α regulates tumor cell growth at least through induction of apoptosis. We have recently demonstrated that IFN-α causes apoptosis through upregulation of TNF-related apoptosis-inducing ligand (TRAIL) in Daudi B lymphoma and U266 myeloma cells. However, other cell lines such as Ramos and RPMI 8226 underwent apoptosis without any apparent involvement of TRAIL following IFN-α stimulation. In this study, we examined whether the IFN-α-induced upregulation of TRAIL is essential for the induction of apoptosis. IFN-α-induced early phase (48 h) of loss of ΔΨm was substantially prevented in Daudi B lymphoma cells overexpressing the dominant-negative form of Fas-associated death domain (dnFADD) compared with vector control, whereas a late phase (72 h) of ΔΨm was comparable to the control. The IFN-α-induced early phase of apoptosis was also reduced in the dnFADD-expressing cells, while the late phase of apoptosis was unaffected. IFN-α-induced upregulation of TRAIL protein in the dnFADD-expressing Daudi or U266 cells was comparable to their control cells, suggesting that FADD is not involved in the IFN-α-induced upregulation of TRAIL. Moreover, the early phase of mitochondrial depolarization was severely prevented by the presence of fusion protein of TRAIL receptor 1 and Fc portion of immunoglobulin (TRAIL-R1:Fc) and TRAIL-R2:Fc. Together, IFN-α induces apoptosis in a TRAIL-dependent or -independent manner, depending on the course of the apoptotic process.

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