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

Noriko Yanase1, Miho Hayashida, Yuki Kanetaka-Naka

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

BMC Cell Biology
|March 23, 2012
PubMed
Abstract

Insights

Interferon-alfa (IFN-α) activates JNK1 through PKC-δ, upregulating TRAIL and inducing apoptosis in B lymphoma cells. This pathway is crucial for IFN-α

Area of Science:

  • Oncology
  • Cell Biology
  • Immunology

Background:

  • Interferon-alfa (IFN-α) exhibits anti-tumor properties, including apoptosis induction in B lymphoma cells.
  • IFN-α triggers sustained activation of c-Jun NH₂-terminal kinase1 (JNK1), a key player in tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter activation.
  • The upstream signaling components responsible for prolonged IFN-α-induced JNK1 activation require elucidation.

Purpose of the Study:

  • To investigate the upstream signaling pathway mediating sustained JNK1 activation by IFN-α.
  • To determine the role of protein kinase C delta (PKC-δ) in IFN-α-induced JNK1 activation and subsequent apoptotic events.

Main Methods:

  • Western blotting to detect phosphorylated PKC-δ in IFN-α-treated B lymphoma and myeloma cells.
  • Utilized dominant-negative PKC-δ (dnPKC-δ) and PKC-δ inhibitor rottlerin to assess JNK1 activation, TRAIL promoter activity, and apoptosis markers.
  • Employed a constitutively active PKC-δ mutant to evaluate its effect on IFN-α-induced TRAIL promoter activity and mitochondrial membrane potential.

Main Results:

  • IFN-α activated PKC-δ in Daudi B lymphoma and U266 myeloma cells.
  • dnPKC-δ and rottlerin significantly attenuated IFN-α-induced JNK1 activation, TRAIL promoter activity, and apoptotic markers (loss of mitochondrial membrane potential, increased propidium iodide uptake).
  • Constitutively active PKC-δ enhanced IFN-α-induced TRAIL promoter activity and mitochondrial dysfunction, while dnPKC-δ abrogated IFN-α-induced Ser727 phosphorylation of Stat1.

Conclusions:

  • IFN-α activates JNK1 via PKC-δ, leading to TRAIL upregulation and subsequent apoptosis in B lymphoma cells.
  • The PKC-δ-mediated signaling pathway, including Stat1 phosphorylation, contributes to IFN-α-induced apoptotic events.
  • This study elucidates a novel signaling cascade involving PKC-δ and JNK1 in IFN-α-mediated anti-cancer effects.

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