cAMP-responsive Element Modulator (CREM)α Protein Induces Interleukin 17A Expression and Mediates Epigenetic Alterations at the Interleukin-17A Gene Locus in Patients with Systemic Lupus Erythematosus

Rauen, Thomas; Hedrich, Christian M.; Juang, Yuang-Taung; Tenbrock, Klaus; Tsokos, George C.

doi:10.1074/jbc.m111.299313

Cited by 120 publications

(141 citation statements)

References 44 publications

(58 reference statements)

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“…Forced expression of CREMα in primary human T cells mediated cytokine expression patterns that are similar to those of effector memory phenotypes. This may, in part, be due to trans-activating effects of CREMα on IL17A promoter activity (8,15,15) and trans-repressing effects on the IL2 promoter through replacement of the activating transcription factor pCREB (12). However, here we demonstrate additional effects of CREMα on CpG-DNA methylation of the IL2 and IL17A promoter during T-cell priming.…”

Section: Discussioncontrasting

confidence: 44%

“…We previously reported that CREMα trans-activates the IL17A proximal promoter in T cells from SLE patients (15). In the present study, we investigated whether CREMα mediates epigenetic modifications to the IL17A promoter during T-cell differentiation.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that IL-17A expression in T cells from SLE patients is supported by epigenetic remodeling of the IL17A gene (15). To better understand the regulation of IL17A during T-cell lineage determination, we investigated CpG-DNA methylation in human naive, central memory, and effector memory CD4 + T cells.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate CpG-DNA methylation patterns across the human IL2 and IL17A genes, we defined regions of interest as reported previously (8,15). We aligned the mouse and human IL2 and IL17A genes (VISTA Genome Browser, http://pipeline.lbl.gov/cgi-bin/gateway2), and determined conserved noncoding sequences (CNS), exons, and UTRs.…”

Section: Resultsmentioning

confidence: 99%

“…T cells from SLE patients are characterized by severe signaling anomalies resulting in altered cytokine production (14). CREMα has been linked to reduced IL-2 and increased IL-17A expression through diametric trans-regulatory effects on the IL2 and IL17A genes (8,(15)(16)(17). CREMα expression is controlled by trans-activation and trans-repression of the CREM promoter P1 (9,10).…”

Section: Inflammation | Gene Regulationmentioning

confidence: 99%

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cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Hedrich

Crispín

Rauen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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119

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Appropriate expression of IL-2 plays a central role during the priming and differentiation of T cells. A tight balance between IL-2 and the effector cytokine IL-17A is essential for immune homeostasis. Epigenetic mechanisms have been documented as a key component of cytokine regulation during lineage commitment. The molecular mechanisms that induce chromatin remodeling are less well understood. We investigated epigenetic regulators that mediate the diametric expression of IL-2 and IL-17A in naive, central memory, and effector memory CD4 + T cells. We demonstrate that cAMP response modulator (CREM)α contributes to epigenetic remodeling of IL2 in effector memory T cells through the recruitment of DNMT3a. CREMα also reduces CpG-DNA methylation of the IL17A promoter. CREMα expression is regulated at the epigenetic level by CpG-DNA methylation, which allows increased CREMα expression in effector memory CD4 + T cells. T cells from patients with systemic lupus erythematosus (SLE) express increased levels of CREMα and exhibit a phenotype that is similar to effector memory CD4 + T cells with epigenetically predetermined expression patterns of IL-2 and IL-17A. We conclude that CREMα mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease.inflammation | gene regulation

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Section: Discussioncontrasting

confidence: 44%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Inflammation | Gene Regulationmentioning

confidence: 99%

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cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Hedrich

Crispín

Rauen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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119

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Silicon‐Based Biomaterials Modulate the Adaptive Immune Response of T Lymphocytes to Promote Osteogenesis/Angiogenesis via Epigenetic Regulation

Xia,

Wu,

Chen

et al. 2023

Adv Healthcare Materials

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Silicon (Si)‐based biomaterials have been widely applied for bone regeneration. However, the underlying mechanisms of the materials function remain largely unknown. T lymphocyte‐mediated adaptive immune response plays a vital role in the process of bone regeneration. In the current study, mesoporous silica (MS) was used as a model material of Si‐based biomaterials. It showed that the supernatant of CD4+ T lymphocytes pretreated with MS extract significantly promoted the vascularized bone regeneration. The potential mechanism is closely related to the fact that MS extract could reduce the expression of regulatory factor X‐1 (RFX‐1) in CD4+ T lymphocytes. This might result in the overexpression of interleukin‐17A (IL‐17A) by boosting histone H3 acetylation and lowering DNA methylation and H3K9 trimethylation. Importantly, the in vivo experiments further revealed that MS particles significantly enhanced bone regeneration with improved angiogenesis in the critical‐sized calvarial defect mouse model accompanied by upregulation of IL‐17A in peripheral blood and the proportion of Th17 cells. Our study suggests that modulation of the adaptive immune response of T lymphocytes by Silicate‐based biomaterials plays an important role for bone regeneration.This article is protected by copyright. All rights reserved

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Cyclic adenosine monophosphate–responsive element modulator alpha overexpression impairs function of hepatic myeloid‐derived suppressor cells and aggravates immune‐mediated hepatitis in mice

Hammerich¹,

Warzecha²,

Stefkova³

et al. 2015

Hepatology

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Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate-responsive element modulator alpha (CREMa) can endorse differentiation of T lymphocytes toward T-helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMa in liver disease, we subjected transgenic (Tg) mice overexpressing CREMa under control of the CD2 promoter (crem tg mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREMa overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem tg mice developed more severe immune-mediated hepatitis with a higher mortality rate, compared to wild-type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMa overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem tg CD4 1 T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1 2/2 mice with Crem 2/2 T cells did not ameliorate ConA hepatitis. Overexpression of CREMa did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREMa. Crem tg MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune-mediated liver damage in crem tg mice to wt level. Conclusion: These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMa in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease. (HEPATOLOGY 2015;61:990-1002) A utoimmune hepatitis (AIH) has a wide spectrum of clinical presentations, ranging from asymptomatic disease, acute or chronic hepatitis, to fulminant hepatic failure, and is characterized by intrahepatic lymphocyte activation, interface hepatitis, circulating autoantibodies, hypergammaglobulinemia, and a favorable response to immunosuppression. 1In concordance with other autoimmune diseases, AIH is associated with non-organ-specific antibodies (Abs), such as antinuclear Abs, in the context of hepatic

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cAMP-responsive Element Modulator (CREM)α Protein Induces Interleukin 17A Expression and Mediates Epigenetic Alterations at the Interleukin-17A Gene Locus in Patients with Systemic Lupus Erythematosus

Cited by 120 publications

References 44 publications

cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Silicon‐Based Biomaterials Modulate the Adaptive Immune Response of T Lymphocytes to Promote Osteogenesis/Angiogenesis via Epigenetic Regulation

Cyclic adenosine monophosphate–responsive element modulator alpha overexpression impairs function of hepatic myeloid‐derived suppressor cells and aggravates immune‐mediated hepatitis in mice

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