Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells

Helms, Whitney S.; Jeffrey, Jerry; Holmes, Derek A; Townsend, Michael; Clipstone, Neil A.; Su, Lishan

doi:10.1189/jlb.0206120

Cited by 22 publications

(18 citation statements)

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“…Considering the observed up‐regulated expression of RhoA mRNA and down‐regulated expression of miR‐31 and IL‐2 in lupus T cells, along with the regulatory role of RhoA in modulating IL2 gene expression in T cells (33), we hypothesized that miR‐31 regulates the expression of IL‐2 in T cells by targeting RhoA. If this is the likely scenario, then the inhibition of RhoA expression would have an effect equivalent to that caused by the overexpression of miR‐31.…”

Section: Resultsmentioning

confidence: 99%

“…Down‐regulated miR‐31 expression resulted in high levels of RhoA, a target of miR‐31 in SLE. RhoA, a small GTPase that is well characterized for its role in cytoskeletal rearrangement, has been shown to inhibit IL‐2 production in T cells and regulate the IL2 promoter in an NF‐AT–dependent manner (33, 38). Our investigation showed that siRNA‐mediated knockdown of RhoA enhanced the IL2 promoter activity and IL‐2 production in T cells.…”

Section: Discussionmentioning

confidence: 99%

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Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Fan¹,

Liang²,

Tang³

et al. 2012

Arthritis & Rheumatism

100

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Objective. MicroRNAs (miRNAs) function to finetune the control of immune cell signaling. It is well established that there are abnormalities in the interleukin-2 (IL-2)-related signaling pathways in systemic lupus erythematosus (SLE). The miR-31 micro-RNA has been found to be markedly underexpressed in patients with SLE, and thus the present study was undertaken to investigate the role of miR-31 in IL-2 defects in lupus T cells.Methods. Expression levels of miR-31 were quantitated using TaqMan miRNA assays. Transfection and stimulation of cultured cells followed by TaqMan quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and reporter gene assays were conducted to determine the biologic function of miR-31. NF-AT nuclear translocation and expression were quantitatively measured using an ImageStream cytometer. Bioinformatics analysis, small interfering RNA (siRNA) knockdown, and Western blotting were performed to validate miR-31 targets and effects.Results. The expression of miR-31 was significantly decreased in lupus T cells, and this was positively correlated with the expression of IL-2. Overexpression of miR-31 in T cells increased the production of IL-2 by altering NF-AT nuclear expression and IL2 promoter activity, while knockdown of endogenous miR-31 reduced IL-2 production. RhoA expression was directly repressed by miR-31 in T cells. Of note, siRNA-mediated knockdown of RhoA enhanced IL2 promoter activity and, consequently, up-regulated IL-2 production. RhoA expression was consistently up-regulated and negatively correlated with the levels of miR-31 in lupus T cells. Manipulation of miR-31 expression in lupus T cells restored the expression of IL-2 at both the messenger RNA and protein levels.Conclusion. MicroRNA-31 is a novel enhancer of IL-2 production during T cell activation. Dysregulation of miR-31 and its target, RhoA, could be a novel molecular mechanism underlying the IL-2 deficiency in patients with SLE.Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder characterized by chronic

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Fan¹,

Liang²,

Tang³

et al. 2012

Arthritis & Rheumatism

100

View full text Add to dashboard Cite

show abstract

“…Intriguingly, the effect did not affect NFAT nuclear translocation or DNA binding, but its presence caused a decrease in histone-3 acetylation at the IL2 promoter. Therefore, RhoA activation may affect local chromatin remodeling and the ability of NFAT to transactivate DNA transcription [6]. Further work is needed to establish if this molecule plays a role in the physiologic regulation of IL-2.…”

Section: New Factors and Chromatin Remodeling In The Il2 Promotermentioning

confidence: 99%

Transcriptional regulation of IL-2 in health and autoimmunity

Crispín

Tsokos

2009

Autoimmunity Reviews

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The regulation of IL-2 production is central to our understanding of the immune system. Key during T cell activation, it also plays an essential role in the regulation of the immune response. This review discusses the function of recently described factors that modulate transcription and chromatin remodeling at the IL2 promoter. Also, it addresses the role of FoxP3 as a transcriptional regulator in conventional T cells and regulatory T cells, and the mechanisms whereby CD28 stabilizes IL2 transcription and translation. Finally, the alterations that prevent T cells from SLE patients from producing normal amounts of IL-2 upon stimulation are described. Keywords Chromatin remodeling; FoxP3; IL-2; Systemic Lupus Erythematosus; Transcriptional regulationThe importance of IL-2 as a key cytokine for T cell activation and immune function has extensive experimental support [1]. It plays a role as an auto-and paracrine growth factor during the first 48 to 72 hours of T cell activation. Paradoxically, its absence has been linked to development of lethal autoimmunity in mice [1], and failure to produce normal amounts of IL-2 upon activation is considered a hallmark of T cells from patients with systemic lupus erythematosus (SLE), a chronic autoimmune disease [2]. This apparent contradiction -the development of autoimmune disease caused by the absence of a cytokine believed to be central in T cell activation-has been partially explained by the fact that conditions in which IL-2 is absent lack regulatory T cells [3]. In humans, where the deficiency is not absolute, regulatory T cell function has been reported to be abnormal [4], however the significance of such defect within the complex immune deregulation of patients with SLE remains to be determined. Abnormal control of IL-2 production is expected to impact a number of immune cell functions besides those directly related to regulatory T cells. Accordingly, several T cell defects known to be present in patients with SLE (e.g. defective activation-induced cell death and cytotoxic activity), are probably the result of faulty IL-2 production [2]. The knowledge of the mechanisms that regulate IL-2 production in normal and diseased T cells is central to our understanding of complex autoimmune diseases such as SLE. Furthermore, it will allow us to better comprehend the relationship between the effector and regulatory arms of the immune response. The aim of this review is to analyze recent developments that have modified current perspectives of il2 transcriptional regulation.Corresponding author: George C. Tsokos, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, 4 Blackfan Circle, HIM-244, Boston, MA 02115, USA., Phone: 617-667-0751; Fax 617-975-5299, gtsokos@bidmc.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof be...

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“…Finally, MRTF-A activity is impacted by the reorganization of actin filaments as a result of RhoA activation (Olson and Nordheim, 2010). Several reports have suggested that RhoA signaling might be transmitted to the nucleus to influence differential recruitment of epigenetic factors and gene expression (Helms et al, 2007;Kim et al, 2005;Ling and Lobie, 2004). The question as to whether MRTF-A serves as the moderator linking cytoskeletal dynamics and epigenetic regulation of proinflammatory genes is certainly worth further investigation.…”

Section: Research Articlementioning

confidence: 99%

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

Weng

Peng

et al. 2014

Journal of Cell Science

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Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong pro-inflammatory response in macrophages via the transcription factor NF-κB. The epigenetic mechanism underlying LPS-induced pro-inflammatory transcription is not completely appreciated. Herein we describe a role for myocardin related transcription factor A, or MRTF-A, in this process. MRTF-A over-expression potentiated while MRTF-A silencing dampened NF-κB dependent pro-inflammatory transcription. MRTF-A deficiency also alleviated the synthesis of pro-inflammatory mediators in a mouse model of colitis. LPS promoted the recruitment of MRTF-A to the promoters of pro-inflammatory genes in a NF-κB dependent manner. Reciprocally, MRTF-A influenced the nuclear enrichment and target binding of NF-κB. Mechanistically, MRTF-A was necessary for the accumulation of active histone modifications on NF-κB target promoters by communicating with the histone H3K4 methyltransferase complex (COMPASS). Silencing of individual members of COMPASS, including ASH2, WDR5, and SET1, down-regulated the production of pro-inflammatory mediators and impaired the NF-κB kinetics. In summary, our work has uncovered a previously unknown function for MRTF-A and provided insights into the rationalized development of anti-inflammatory therapeutic strategies.

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Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells

Cited by 22 publications

References 50 publications

Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Transcriptional regulation of IL-2 in health and autoimmunity

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

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