Amino acid deprivation links BLIMP-1 to the immunomodulatory enzyme indoleamine 2,3-dioxygenase

Nicholas A Barnes, Sophie J Stephenson, Reuben M Tooze, Gina M Doody

Research output: Contribution to journalArticlepeer-review

Abstract

Catabolism of tryptophan by IDO1 plays an important role in the control of immune responses. Activation of the eukaryotic initiation factor 2alpha (eIF2alpha) kinase general control nonderepressible-2 (GCN2) following tryptophan depletion is a major pathway mediating this effect. However, immunomodulatory target genes of GCN2 activation are poorly defined. The transcriptional repressor B lymphocyte-induced maturation protein-1 (BLIMP-1) is a target of the eIF2alpha kinase1, protein kinase-like ER kinase (PERK) during the unfolded protein response of the endoplasmic reticulum. Thus, BLIMP-1 might also be a mediator of the GCN2 stress response pathway activated by IDO1 and tryptophan depletion. Indeed, in human monocytes BLIMP-1 mRNA and protein are up-regulated in response to both a pharmacological activator of GCN2 and tryptophan-depletion generated by IDO1-transfected cells. This suggests a functional role for BLIMP-1 in the immunomodulatory effects of the IDO1-GCN2 axis. BLIMP-1 has been shown to repress IFN-gamma-regulated promoters. As IDO1 is itself highly responsive to IFN-gamma, we hypothesized that BLIMP-1 functions in a feedback loop to regulate IDO1 expression. We found that BLIMP-1 binds to IFN-responsive sites in the IDO1 promoter and represses IFN-dependent IDO1 activation. We propose that BLIMP-1 acts in a negative feedback loop to successfully balance the outcome of tolerance vs inflammation.

Original languageEnglish
Pages (from-to)5768-77
Number of pages10
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume183
Issue number9
DOIs
Publication statusPublished - 1 Nov 2009

Keywords

  • HeLa Cells
  • Humans
  • Immune Tolerance
  • Immunomodulation
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Inflammation Mediators
  • Interferon-gamma
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Repressor Proteins
  • Tryptophan
  • U937 Cells
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't

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