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Open Access Research article

PKC-δ mediates interferon-α-induced apoptosis through c-Jun NH2-terminal kinase activation

Noriko Yanase1, Miho Hayashida12, Yuki Kanetaka-Naka12, Akinori Hoshika2 and Junichiro Mizuguchi1*

Author affiliations

1 Department of Immunology and Intractable Immune System Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan

2 Department of Pediatrics, Tokyo Medical University Hospital, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

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Citation and License

BMC Cell Biology 2012, 13:7  doi:10.1186/1471-2121-13-7

Published: 21 March 2012

Abstract

Background

Interferon-α (IFN-α) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-α induced a sustained activation of c-Jun NH2-terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-α-initiated activation of JNK1.

Results

IFN-α caused activation of PKC-δ in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-δ. The dominant-negative form of mutant PKC-δ (dnPKC-δ) reduced the IFN-α-induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (ΔΨm), and increase in propidium iodide (PI) positive cells. The IFN-α-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-δ inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-δ enhanced the IFN-α-induced TRAIL promoter activity and loss of ΔΨm in Daudi B lymphoma cells. In addition, IFN-α-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-δ.

Conclusions

IFN-α induced JNK1 activation via PKC-δ, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of ΔΨm and increase in PI positive cells. The IFN-α-induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC-δ-mediated signaling component(s).

Keywords:
Interferon-α; PKC-δ; JNKs; Apoptosis; B lymphoma cells