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.
Barnes
Nicholas A
NA
Section of Experimental Haematology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom.
Stephenson
Sophie J
SJ
Tooze
Reuben M
RM
Doody
Gina M
GM
D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D056747:Immunomodulation / Q000235:genetics / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D020298:U937 Cells
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D012097:Repressor Proteins; C087042:PRDM1 protein, human; C069544:tryptophanol; D007371:Interferon-gamma; D014364:Tryptophan; D000074462:Positive Regulatory Domain I-Binding Factor 1; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases