Synergistic transcriptional activation of indoleamine dioxygenase by IFN-gamma and tumor necrosis factor-alpha

J Interferon Cytokine Res. 2003 Aug;23(8):413-21. doi: 10.1089/107999003322277829.

Abstract

Interferon-gamma (IFN-gamma)-induced indoleamine 2,3-dioxygenase (IDO) activity inhibits the growth of susceptible intracellular pathogens by catalyzing the oxidative cleavage of the indole ring of L-tryptophan and depleting pools of the essential amino acid. Tumor necrosis factor-alpha (TNF-alpha) synergistically enhances the IDO activity induced by IFN-gamma at the level of transcription in human epithelial cells. The purpose of this study was to characterize the molecular mechanisms responsible for synergistic gene expression in response to IFN-gamma and TNF-alpha. It was found that IFN-gamma-induced mechanisms, such as the binding of Stat1 to gamma activation sequences (GAS) and IFN regulatory factor-1 (IRF-1) to IFN-stimulated response elements (ISREs), are more highly activated following treatment with IFN and TNF-alpha. This enhanced signal transduction may be due to the increase in IFN-gamma receptor (IFNGR) expression following combined cytokine stimulation and is a likely contributor to the synergy. Additionally, the contribution of a third previously uncharacterized GAS element that forms a complex with Stat1 was investigated using a plasmid reporter system that controls for copy number. When the GAS-3 sequence was included in the regulatory region, gene expression was significantly increased relative to a region containing the mutated GAS-3. This suggests that GAS-3 is transcriptionally active and contributes to IFN-gamma-induced regulation of the IDO gene.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Binding Sites
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / metabolism
  • Drug Synergism
  • Enzyme Induction
  • HeLa Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interferon Regulatory Factor-1
  • Interferon-gamma / pharmacology*
  • Phosphoproteins / metabolism
  • Receptors, Interferon / metabolism
  • Response Elements
  • Transcription Factors / metabolism
  • Transcriptional Activation*
  • Tryptophan Oxygenase / biosynthesis
  • Tryptophan Oxygenase / genetics*
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • DNA-Binding Proteins
  • IRF1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interferon Regulatory Factor-1
  • Phosphoproteins
  • Receptors, Interferon
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • interferon gamma receptor
  • Interferon-gamma
  • Tryptophan Oxygenase