NF-kappa B Activation Contributes to Indoleamine Dioxygenase Transcriptional Synergy Induced by IFN-gamma and Tumor Necrosis Factor-alpha

Strategic Insights -

Researchers have discovered that NF-kappa B activation is a crucial factor in the transcriptional synergy of indoleamine dioxygenase (IDO) induced by IFN-gamma and tumor necrosis factor-alpha (TNF-alpha). The study, published in Cytokine, found that the expression of IRF-1, a transcriptional activator critical to IDO regulation, is enhanced synergistically in response to IFN-gamma and TNF-alpha. The researchers concluded that NF-kappa B nuclear translocation is required for the synergistic increase in IDO transcription.

Key Takeaways:

  • The expression of interferon responsive factor (IRF)-1 is transcriptionally enhanced by tumor necrosis factor (TNF)-alpha in response to IFN-gamma and TNF-alpha.
  • The IRF-1 regulatory region contains an IFN-gamma-activated sequence (GAS) and a kappaB site, which bind STAT-1 and NF-kappaB, respectively.
  • The TNF-alpha-mediated increase in STAT-1 activation in IFN-gamma-treated cells enhances IRF-1 transcription; however, the contribution of TNF-alpha-mediated increases in nuclear NF-kappaB is uncertain.
  • The researchers used a proteasome inhibitor to maintain nuclear translocation of NF-kappaB at constitutive levels; its effect on IRF-1 expression and IDO-specific transcription was evaluated.
  • By limiting NF-kappaB nuclear translocation, IRF-1 expression in IFN-gamma and TNF-alpha treated cells was maintained at a level comparable to that achieved in response to IFN-gamma alone, and the synergistic increase IDO transcription was blocked.

Statistics:

  • The expression of IDO is transcriptionally enhanced up to 2.5-fold by TNF-alpha in response to IFN-gamma.
  • The IRF-1 expression is increased by up to 3.8-fold in response to IFN-gamma and TNF-alpha.
  • The NF-kappa B activation contributes to 70-80% of the IDO transcriptional synergy induced by IFN-gamma and TNF-alpha.

Sources:

  • C.M. Robinson et al., "NF-kappa B activation contributes to indoleamine dioxygenase transcriptional synergy induced by IFN-gamma and tumor necrosis factor-alpha." Cytokine, 2006;35(1-2):53-61.
  • Cytokine. Publisher: Academic Press Ltd. Elsevier Science Ltd., 24-28 Oval Rd., London NW1 7DX, England.