Inhibition of interferon-γ-activated nuclear factor-κB by cyclosporin A: A possible mechanism for synergistic induction of apoptosis by interferon-γ and cyclosporin A in gastric carcinoma cells

Kiichiro Beppu, Takashi Morisaki, Hisashi Matsunaga, Akihiko Uchiyama, Eikichi Ihara, Katsuya Hirano, Hideo Kanaide, Masao Tanaka, Mitsuo Katano

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Abstract

We previously reported synergistic induction of apoptosis by IFN-γ plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-γ plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-γ induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-γ alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-γ pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-γ-induced anti-apoptotic pathway and we evaluated the effect of IFN-γ and CsA on calcium-sensitive nuclear factor-κB (NF-κB) activation. IFN-γ increased intracellular calcium ion concentration ([Ca2+]i) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-κB occurred in response to IFN-γ, and which was markedly inhibited by either CsA or FK506. NF-κB decoy also enhanced the cytotoxic effect of IFN-γ. These results suggest that IFN-γ may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-κB and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.

Original languageEnglish
Pages (from-to)797-805
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume305
Issue number4
DOIs
Publication statusPublished - Jun 13 2003

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All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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