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Feedback inhibition of indoleamine 2,3‐dioxygenase by BLIMP‐1 in response to tryptophan depletion
Author(s) -
Barnes Nicholas,
Stephenson Sophie,
Tooze Reuben,
Doody Gina
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1065.20
Subject(s) - indoleamine 2,3 dioxygenase , unfolded protein response , microbiology and biotechnology , repressor , endoplasmic reticulum , activator (genetics) , kinase , regulation of gene expression , biology , corepressor , chemistry , transcription factor , gene , tryptophan , biochemistry , amino acid
BLIMP‐1 protein expression is up‐regulated in the myeloid cell lineage during differentiation and, as previously shown by us, as part of the unfolded protein response downstream of endoplasmic reticulum stress and PERK activation. We hypothesized that BLIMP‐1 would also be implicated in the signaling pathways activated in response to alternative cellular stresses. Indoleamine 2,3‐dioxygenase (IDO) is an immunoregulatory enzyme that depletes tryptophan from the surrounding tissue microenvironment, thereby inducing amino acid starvation and activation of the stress kinase GCN2. Using transfection studies and tryptophan‐depleted media we found that PRDM1 , the gene encoding BLIMP‐1 protein, was induced, and that a pharmacologic activator of the GCN2 response caused an up‐regulation of BLIMP‐1 protein in the monocytic U937 cell line. Furthermore, BLIMP‐1 is a transcriptional repressor and has two potential consensus target sites in the IDO promoter. Analysis of BLIMP‐1 binding to these regions of the IDO promoter indicates that BLIMP‐1 is not only capable of binding here, but that BLIMP‐1 also inhibits IFNγ‐induced up‐regulation of the IDO gene. We propose that BLIMP‐1 may function in a negative feedback role to regulate IDO levels in cell types that express these two proteins, thereby maintaining the expression of IDO at a level that successfully balances the outcome of tolerance versus inflammation.