Interferon-alpha-induced apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent and -independent manner.
IFN-alpha regulates tumor cell growth at least through induction of apoptosis. We have recently demonstrated that IFN-alpha 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-alpha stimulation. In this study, we examined whether the IFN-alpha-induced upregulation of TRAIL is essential for the induction of apoptosis. IFN-alpha-induced early phase (48 h) of loss of DeltaPsim 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 DeltaPsim was comparable to the control. The IFN-alpha-induced early phase of apoptosis was also reduced in the dnFADD-expressing cells, while the late phase of apoptosis was unaffected. IFN-alpha-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-alpha-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-alpha induces apoptosis in a TRAIL-dependent or -independent manner, depending on the course of the apoptotic process.
Yanase
Noriko
N
Department of Immunology and Intractable Disease Research Center, Tokyo Medical University, Tokyo 160-8402, Japan.
Kanetaka
Yuki
Y
Mizuguchi
Junichiro
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015153:Blotting, Western; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005434:Flow Cytometry; D005799:Genes, Dominant; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013347:Subcellular Fractions; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation