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

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.
Mesh Terms:
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
J. Immunol.
Date: Nov. 01, 2009
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