HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0803480v1 183/9/5768    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Barnes, N. A. Articles by Doody, G. M. PubMed PubMed Citation Articles by Barnes, N. A. Articles by Doody, G. M.

Amino Acid Deprivation Links BLIMP-1 to the Immunomodulatory Enzyme Indoleamine 2,3-Dioxygenase¹

Section of Experimental Haematology, Leeds Institute of Molecular Medicine, St James’s University Hospital, Leeds, United Kingdom

Catabolism of tryptophan by IDO1 plays an important role in the control of immune responses. Activation of the eukaryotic initiation factor 2 (eIF2) 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 eIF2 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--regulated promoters. As IDO1 is itself highly responsive to IFN-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a New Investigator Grant (BB/E000746/1) from the U.K. Biotechnology and Biological Sciences Research Council (to G.M.D.).

² Address correspondence and reprint requests to Dr. Gina M. Doody, Section of Experimental Haematology, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, United Kingdom. E-mail address: medgmd{at}leeds.ac.uk

³ Abbreviations used in this paper: GCN2, general control nonderepressible-2; eIF2, eukaryotic initiation factor 2; HRI, heme-regulated inhibitor; ER, endoplasmic reticulum; PERK, protein kinase-like ER kinase; BLIMP-1, B lymphocyte-induced maturation protein-1; IRF-E, IFN regulatory factor-element; IRF, IFN regulatory factor; FL, full length; siRNA, small interfering RNA; wt, wild type; CHOP, C/EBP homologous protein; XBP-1, X-box binding protein 1; ISRE, IFN-stimulated response element; ChIP, chromatin immunoprecipitation.