Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

Tooze, Reuben; Stephenson, Sophie; Doody, Gina M.

doi:10.4049/jimmunol.177.7.4584

Cited by 29 publications

(63 citation statements)

References 46 publications

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“…This footprinting assay also detected protein-DNA interactions in myeloma cells at the CIITA pIV IRF-E site that are similar before and after treatment with IFN-γ. We and others have recently demonstrated that the CIITA pIV IRF-E site is a binding site for the PRD-IBF1/Blimp-1 repressor (Tooze et al, 2006;Chen et al, 2007). It is possible that PRD-IBF1/Blimp-1 binds the IRF-E site in untreated myeloma cells and that this binding is replaced after treatment with IFN-γ by IRF-1 and IRF-2, which make similar contacts at this site and activate CIITA pIV expression.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently demonstrated CIITA type IV promoter activity that is up regulated by IFN-γ in B lymphocytes (Piskurich et al, 2006). We and others have also recently shown that this promoter, like pIII, is a candidate for repression by PRDI-BF1/Blimp-1 (Tooze et al, 2006;Chen et al, 2007). Since CIITA regulation is complex and cell-type specific, understanding its regulation in multiple myeloma requires the study of mechanisms of CIITA transcription as they relate specifically to these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Since myeloma cells express PRDI-BF1/Blimp-1, they also generally express low constitutive levels of CIITA and MHC II (Nagy et al, 2002). We and others have recently described the IFN-γ-inducible CIITA promoter, pIV, as a new target for repression by PRDIBF1/Blimp-1 (Tooze et al, 2006;Chen et al, 2007). Although they express PRDI-BF1/Blimp-1, increases in MHC II expression in response to IFN-γ have been described both in vivo and in vitro for myeloma cells (Yi et al, 1997;Beatty and Paterson, 2001).…”

Section: Introductionmentioning

confidence: 99%

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MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Zhao

Flynt

Hong

et al. 2007

Molecular Immunology

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The MHC Class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-γ in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI-pIV) of this gene. To investigate regulation of CIITA by IFN-γ in multiple myeloma cells, first the ability of these cells to respond to IFN-γ was examined. RTPCR analyses show that IFN-γR1, the IFN-γ-binding chain of the IFN-γ receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-γ treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-γ. RT-PCR and functional promoter analyses show that IFN-γ up regulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to up regulate CIITA pIV and MHC II expression in response to IFN-γ treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-γ.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

Zhao

Flynt

Hong

et al. 2007

Molecular Immunology

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“…Expression vectors encoding full-length (FL) BLIMP-1, IRF-1, and IRF-2 have been described previously (30). An expression vector encoding IDO1 was generated by amplifying cDNA using primers (5Ј-ATAGAATTCG CCACCATGGCACACGCTATGGA-3Ј and 5Ј-ATATGTCGACTTAACC TTCCTTCAAAA-3Ј) and cloned into the modified pIRES2-EGFP vector incorporating an N-terminal Myc epitope tag as previously described (30).…”

Section: Expression Vectors and Transfectionsmentioning

confidence: 99%

“…Work from our laboratory has shown that BLIMP-1 is indeed capable of repressing genes regulated by IFN-␥ (30,31). In these examples, BLIMP-1 mediates repression through direct competition with IFN regulatory factors (IRFs) at the IRF-E sites contained within their promoters.…”

mentioning

confidence: 99%

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

Barnes

Stephenson

Tooze

et al. 2009

The Journal of Immunology

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Catabolism of tryptophan by IDO1 plays an important role in the control of immune responses. Activation of the eukaryotic initiation factor 2α (eIF2α) 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 eIF2α 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-γ-regulated promoters. As IDO1 is itself highly responsive to IFN-γ, 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.

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Distinct regulation of MHC molecule expression on astrocytes and microglia during viral encephalomyelitis

Hamo

Stohlman

Otto‐Duessel

et al. 2007

Glia

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The potential interplay of glial cells with T cells during viral induced inflammation was assessed by comparing major histocompatibility complex molecule upregulation and retention on astrocytes and microglia. Transgenic mice expressing green fluorescent protein under control of the astrocyte-specific glial fibrillary acidic protein promoter were infected with a neurotropic coronavirus to facilitate phenotypic characterization of astrocytes and microglia using flow cytometry. Astrocytes in the adult central nervous system up-regulated class I surface expression, albeit delayed compared with microglia. Class II was barely detectable on astrocytes, in contrast to potent up-regulation on microglia. Maximal MHC expression in both glial cell types correlated with IFN-gamma levels and lymphocyte accumulation. Despite a decline of IFN-gamma concomitant to virus clearance, MHC molecule expression on glia was sustained. These data demonstrate distinct regulation of both class I and class II expression by microglia and astrocytes in vivo following viral induced inflammation. Furthermore, prolonged MHC expression subsequent to viral clearance implies a potential for ongoing presentation.

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Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

Cited by 29 publications

References 46 publications

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ

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

Distinct regulation of MHC molecule expression on astrocytes and microglia during viral encephalomyelitis

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