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IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha

Takaya Tsuno1, Josef Mejido, Tongmao Zhao

  • 1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Journal of Immunotherapy (Hagerstown, Md. : 1997)
|September 16, 2009
PubMed

Insights

Interferon-alpha (IFN-alpha) resistance in tumors can be overcome by targeting Interferon Regulatory Factor 9 (IRF9). IRF9 is key for IFN-alpha

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Human interferon-alpha (IFN-alpha) exhibits limited antiproliferative effects on certain tumors.
  • The Janus kinases/Signal Transducers and Activators of Transcription (JAK-STAT) pathway is crucial for initial IFN signaling.
  • Identifying key JAK-STAT pathway factors is essential to enhance IFN-alpha's antiproliferative activity.

Purpose of the Study:

  • To elucidate the specific roles of JAK-STAT pathway factors in mediating IFN-alpha's antiproliferative activity.
  • To investigate the involvement of Interferon Regulatory Factor 9 (IRF9) and STAT1 in IFN-alpha signaling.
  • To explore the relationship between IRF9, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and IFN-alpha-induced apoptosis.

Main Methods:

  • Utilized RNA interference (RNAi) to inhibit specific genes (IRF9, STAT1, TRAIL-R2) in human ovarian adenocarcinoma (OVCAR3) and glioblastoma (T98G) cells.
  • Assessed the antiproliferative effects of IFN-alpha and IFN-gamma following gene silencing.
  • Analyzed the transcriptional regulation of TRAIL and its interaction with the IFN-stimulated gene factor 3 (ISGF3) complex.
  • Investigated the role of TRAIL-receptor 2 (TRAIL-R2) in mediating IFN-alpha and TRAIL signaling.

Main Results:

  • IRF9-RNAi completely abolished IFN-alpha's antiproliferative activity in OVCAR3 cells, while STAT1-RNAi had no effect.
  • IRF9-RNAi inhibited IFN-alpha-induced TRAIL transcription, suggesting IRF9's critical role in TRAIL induction.
  • IFN-alpha treatment led to the binding of the ISGF3 complex to TRAIL motifs.
  • TRAIL-R2-RNAi impaired the antiproliferative effects of both IFN-alpha and TRAIL.
  • IRF9 overexpression enhanced IFN-alpha-induced apoptosis in IFN-alpha-resistant T98G cells.

Conclusions:

  • IRF9 is identified as the key intracellular factor responsible for mediating the antiproliferative activity of IFN-alpha.
  • TRAIL acts as a potential mediator of IFN-alpha's antiproliferative effects, with IRF9 regulating its transcription.
  • TRAIL-R2 is implicated as a crucial receptor in transmitting both IFN-alpha and TRAIL signals for antiproliferative outcomes.

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