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Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3

Lena Thyrell1, Velmurugesan Arulampalam, Linn Hjortsberg

  • 1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden.

Experimental Cell Research
|September 21, 2007
PubMed

Insights

Interferon alpha (IFNalpha) inhibits STAT3 signaling, a key survival pathway in multiple myeloma. This inhibition leads to apoptosis in myeloma cells, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Multiple myeloma survival often relies on interleukin 6 (IL-6) signaling.
  • IL-6 survival signaling is primarily mediated by Signal Transducer and Activator of Transcription 3 (STAT3) activation.
  • Interferon alpha (IFNalpha) induces apoptosis in multiple myeloma cells.

Purpose of the Study:

  • To investigate the mechanism by which IFNalpha induces apoptosis in multiple myeloma cells.
  • To determine the role of STAT3 signaling in IFNalpha-mediated apoptosis.
  • To explore the interaction between IFNalpha and IL-6/STAT3 pathways in myeloma.

Main Methods:

  • Treatment of multiple myeloma cell lines (U266-1984, U-1958) with IFNalpha.
  • Electrophoretic Mobility Shift Assay (EMSA) to assess STAT3 DNA-binding activity.
  • Analysis of STAT3 target gene expression (Bcl-X(L), Mcl-1, survivin).
  • Ectopic expression of a constitutively active STAT3 mutant (STAT3C).

Main Results:

  • IFNalpha treatment decreased STAT3 DNA-binding activity and shifted STAT complexes from STAT3/3 to STAT1/1 and STAT3/1.
  • This led to down-regulation of STAT3 target genes like Bcl-X(L), Mcl-1, and survivin.
  • Ectopic expression of STAT3C rescued cells from IFNalpha-induced apoptosis, promoting sustained STAT3 activity and up-regulation of Bcl-2 and Mcl-1.

Conclusions:

  • IFNalpha interferes with IL-6 signaling by inhibiting STAT3 activity in multiple myeloma cells.
  • The abrogation of STAT3 activity by IFNalpha is crucial for inducing apoptosis in myeloma.
  • Targeting STAT3 signaling with IFNalpha presents a potential therapeutic approach for multiple myeloma.

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