cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes.

Bodor, Josef; Spetz, Anna-Lena; Strominger, Jack L.; Habener, Joel F.

doi:10.1073/pnas.93.8.3536

Cited by 88 publications

(95 citation statements)

References 26 publications

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“…This finding is further supported by the observations that T cells expressing cyclooxygenase-2 (COX-2) suppress effector Foxp3 -T cells by a PGE 2 -dependent mechanism [12]. Importantly, PGE 2 elevates intracellular levels of cAMP, which is a key physiological inducer of inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) [13][14][15]. ICER/ CREM is also transiently induced by forskolin, which elevates intracellular levels of cAMP [13].…”

Section: Introductionmentioning

confidence: 72%

“…ICER/ CREM is also transiently induced by forskolin, which elevates intracellular levels of cAMP [13]. However, transient, forskolin-mediated induction of ICER, which leads to transcriptional attenuation of IL-2 upon TCR activation [13,14], does not endow T cells with regulatory properties and in fact it down-regulates Foxp3 (our unpublished observations). In contrast, constitutive ICER expression in T cells from mouse made transgenic with ICER showed upon TCR stimulation (i) a profound defect in IL-2 expression and (ii) diminished proliferation either upon TCR activation or in mixed lymphocyte reaction response (MLR) [16].…”

Section: Introductionmentioning

confidence: 82%

“…Importantly, PGE 2 elevates intracellular levels of cAMP, which is a key physiological inducer of inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) [13][14][15]. ICER/ CREM is also transiently induced by forskolin, which elevates intracellular levels of cAMP [13]. However, transient, forskolin-mediated induction of ICER, which leads to transcriptional attenuation of IL-2 upon TCR activation [13,14], does not endow T cells with regulatory properties and in fact it down-regulates Foxp3 (our unpublished observations).…”

Section: Introductionmentioning

confidence: 99%

“…ICER and CREM are synthesized from two distinct promoters of the CREM gene [18]. However, only ICER represents inherent subfamily of transcription repressors in T cells since it is transcribed from internal P2 promoter positioned downstream of CREM activation domain [13]. Therefore, the absence of activation domain makes ICER dominant-negative master regulator playing a pivotal role in suppression of TCRinduced transcription by CD4 + CD25 + T R cells [21] even though definitive experimental proof was not yet firmly established.…”

Section: Introductionmentioning

confidence: 99%

“…S1-S3) [13,14,32]. To investigate further their function in CD25 + CD4 + T R cell-mediated suppression we examined ICER/CREM expression in suppression assays.…”

Section: Introductionmentioning

confidence: 99%

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ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…S1-S3) [13,14,32]. To investigate further their function in CD25 + CD4 + T R cell-mediated suppression we examined ICER/CREM expression in suppression assays.…”

Section: Introductionmentioning

confidence: 99%

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ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Are Astrocytes Central Players in the Pathophysiology of Multiple Sclerosis?

Keyser¹,

Zeinstra²,

Frohman³

2003

Arch Neurol

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An interaction between antimyelin T cells and antigen-presenting glial cells is a crucial step in the cascade of immune events that lead to the inflammatory lesions in multiple sclerosis (MS). One of the most debated and controversial issues is whether microglial cells or astrocytes are the key players in initiating the (auto)immune reactions in the central nervous system in MS. Many investigators consider microglia to be the responsible intrinsic immunoeffector cells. In this review, we speculate that in MS astrocytes may serve as primary (facultative) antigen-presenting cells due to a failure of noradrenergic suppression of class II major histocompatibility complex molecules, which is caused by a loss of beta(2)-adrenergic receptors. If this hypothesis is correct, pharmacologic suppression of the antigen-presenting capacities of astrocytes may be a potential therapy for MS.

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Inducible c AMP Early Repressor

Molina

2002

Wiley Encyclopedia of Molecular Medicine

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cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes.

Cited by 88 publications

References 26 publications

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

Are Astrocytes Central Players in the Pathophysiology of Multiple Sclerosis?

Inducible c AMP Early Repressor

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