The cAMP response element modulator (CREM) regulates TH2 mediated inflammation

Verjans, Eva; Ohl, Kim; Reiss, Lucy Kathleen; Wijk, Femke van; Toncheva, Antoaneta A.; Wiener, Anastasia; Yin, You; Rieg, Annette D.; Gaertner, Vincent D.; Roth, Johannes; Knol, Edward F.; Kabesch, Michael; Wagner, Norbert; Uhlig, Stefan; Martin, Christian; Tenbrock, Klaus

doi:10.18632/oncotarget.6041

Cited by 16 publications

(9 citation statements)

References 52 publications

(67 reference statements)

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“…2b ). These data are in agreement with a previous report according to which ICER/CREM-deficient T cells tend to differentiate towards Th2 more than ICER/CREM-sufficient T cells 11 12 . Decreased numbers of IL-17A-producing cells among Th17-polarized ICER/CREM-deficient T cells were conserved when several IL-6 concentrations were used ( Fig.…”

Section: Resultssupporting

confidence: 94%

ICER is requisite for Th17 differentiation

et al. 2016

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Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

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Section: Resultssupporting

confidence: 94%

ICER is requisite for Th17 differentiation

et al. 2016

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“…Based on RNA-seq data, several dopamine-regulated genes in mouse CD4 + T cells have established disease relevance. For example, among the genes downregulated by dopamine, cAMP-responsive element modulator (CREM) has also been shown to exhibit reduced expression in CD4 + T cells from children with recurrent and persistent wheezing compared with healthy controls (Verjans et al, 2015). In addition, dopamine upregulates Il2ra, Il7r, and Crlf2 (Tlspr), all of which have been identified to be associated with susceptibility to allergic asthma (Ferreira et al, 2017;Sherrill et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Age-Related Dopaminergic Innervation Augments T Helper 2-Type Allergic Inflammation in the Postnatal Lung

et al. 2019

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“…In a negative-feedback fashion, PKA induces reduction of the cytosolic cAMP concentration by directly phosphorylating AC6 in an inhibitory fashion (191) as well as isoforms of PDE3 (192), PDE4 (193, 194), PDE8A (195) in a stimulatory manner. At the transcriptional level, PKA augments the activity of CREB cAMP responsive element binding (CREB), cAMP responsive element modulator (CREM) and activating transcription factor-1 (ATF-1) (196), which induce or counteract the transcription of multiple inflammation-relevant genes such as IL-2 (197–199), IFNγ (200–202), IL-4 and IL-13 (203, 204), IL-17 (205–208), and FoxP3 (209, 210). Specifically, PKA promotes the transcriptional activity of CREB by phosphorylating it thus increasing its affinity for its co-activators CBP and p300 (211), and by promoting the nuclear localization of CRTC (212), another family of CREB co-activators.…”

Section: Adenosine-induced Intracellular Camp Accumulation Impairs T mentioning

confidence: 99%

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

et al. 2019

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T cells play a critical role in cancer control, but a range of potent immunosuppressive mechanisms can be upregulated in the tumor microenvironment (TME) to abrogate their activity. While various immunotherapies (IMTs) aiming at re-invigorating the T-cell-mediated anti-tumor response, such as immune checkpoint blockade (ICB), and the adoptive cell transfer (ACT) of natural or gene-engineered ex vivo expanded tumor-specific T cells, have led to unprecedented clinical responses, only a small proportion of cancer patients benefit from these treatments. Important research efforts are thus underway to identify biomarkers of response, as well as to develop personalized combinatorial approaches that can target other inhibitory mechanisms at play in the TME. In recent years, adenosinergic signaling has emerged as a powerful immuno-metabolic checkpoint in tumors. Like several other barriers in the TME, such as the PD-1/PDL-1 axis, CTLA-4, and indoleamine 2,3-dioxygenase (IDO-1), adenosine plays important physiologic roles, but has been co-opted by tumors to promote their growth and impair immunity. Several agents counteracting the adenosine axis have been developed, and pre-clinical studies have demonstrated important anti-tumor activity, alone and in combination with other IMTs including ICB and ACT. Here we review the regulation of adenosine levels and mechanisms by which it promotes tumor growth and broadly suppresses protective immunity, with extra focus on the attenuation of T cell function. Finally, we present an overview of promising pre-clinical and clinical approaches being explored for blocking the adenosine axis for enhanced control of solid tumors.

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The cAMP response element modulator (CREM) regulates TH2 mediated inflammation

Cited by 16 publications

References 52 publications

ICER is requisite for Th17 differentiation

ICER is requisite for Th17 differentiation

Age-Related Dopaminergic Innervation Augments T Helper 2-Type Allergic Inflammation in the Postnatal Lung

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

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