Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses

Grenningloh, Roland; Kang, Bok Yun; Ho, I‐Cheng

doi:10.1084/jem.20041330

Cited by 118 publications

(164 citation statements)

References 54 publications

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“…The list of transcription factors that activate IL10 production is increasing; however, only a handful of transcription factors are known to repress its expression (23). Transcription factors ETS1 and T-bet repress IL10 expression in Th1 cells, BCL-6 inhibits IL10 production in Th2 cells, MHC class II transactivator (CIITA) negatively regulates IL10 expression in mouse dendritic cells, and BCL-3 represses IL10 production in macrophages (23,(45)(46)(47)(48). However, the quest for master regulators with a direct binding site on the IL10 promoter still remains.…”

Section: Discussionmentioning

confidence: 99%

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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Background: Transcriptional modulation of IL10, a cytokine that blocks phagolysosome maturation, is not well understood. Results: This study demonstrates human IL10 gene repression by direct binding of Rev-erb␣ on Rev-DR2 in the proximal promoter. Conclusion: Rev-erb␣ binds to IL10 proximal promoter, represses expression, and impedes Mycobacterium tuberculosis in human macrophages. Significance: This study provides rationale to target Rev-erb␣ as a therapeutic intervention that might support host defense in tuberculosis.Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erb␣ is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erb␣ in monocytes and macrophages. The nuclear localization of Rev-erb␣ in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erb␣ elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erb␣ overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erb␣ binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erb␣ bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.Macrophages are immune system sentinels with a major role to play in both innate and adaptive immunity. They are the key effectors in antimicrobial defense, atherogenesis, autoimmunity, and many other inflammatory diseases (1). Although the activation, function, classification, and plasticity of these cells have been studied extensively with regard to cellular signaling, the cytokine environment, and surface, cellular, or secretory markers, studies of the underlying molecular mechanism have mostly addressed NF-B (2). Similarly, modulation of macrophage function and alteration of disease pathology by small molecules such as heme, lipids, or drugs such as rifampicin are well understood at the translational level of the effectors (3, 4), but the transcriptional mechanism involving interactions of these ligands with transcriptional molecules and the resulting expression patterns have not been investigated.This study focuses on Rev-erb␣, an adopted orphan nuclear receptor that belongs to the steroid/thyroid hormone receptor superfamily and is a known ...

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Section: Discussionmentioning

confidence: 99%

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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“…Surviving mice and chimeras derived from Ets1-targeted cells exhibit pan-lymphoid defects. These defects include reduced numbers of thymocytes, lymphoid cells in the spleen, and NK and NKT cells; loss of detectable NK and NKT cell activity; decreased proliferation and elevated apoptosis in mature T cells (4,6,40,58); increased differentiation of B cells to plasma cells with elevated serum immunoglobulin M; B-cell receptor signaling defects (12); abnormalities in T-cell receptor (TCR) ␤-selection in thymopoiesis; and an ineffective Th1 response (11,19). Complicating the assessment of Ets1 function is the fact that Ets1-null mice have been studied not only on a mixed genetic background (C57BL/6 ϫ 129Sv) predisposed to autoimmunity (53) but also with a line of Ets1-null mice that expresses a very low level of a neomorphic protein (ϳ1 to 5%) lacking the pointed domain of Ets1 (7,59).…”

mentioning

confidence: 99%

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Higuchi

Bartel

Masuya³

et al. 2007

Molecular and Cellular Biology

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Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1⌬VII (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics, and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1 ⌬VII isoform. Ets1⌬VII homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8 ؉ and CD8 ؉ CD4 ؉ thymocytes were observed. Lymphoid cell (CD19 ؉ , CD4 ؉ , and CD8 ؉ ) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1⌬VII mutants demonstrate lymphocyte maturation defects associated with misregulation of p16 Ink4a , p27Kip1 , and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.

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“…Previous studies in Ets-1 knockout (Ets-1KO) mice have demonstrated the important functions of Ets-1 in development, proliferation, and survival of NK and T cells (18)(19)(20). Furthermore, Ets-1 acts as a cofactor of T-bet and is essential for Th1 effector function and differentiation by regulating IFN-g expression (21). Ets-1 is a negative regulator of Th17 differentiation, and Th17 cells deficient of Ets-1 express increased IL-17 and IL-17-related cytokines (22).…”

Section: Naive Cd4mentioning

confidence: 99%

“…Flag-Ets-1 plasmid was described previously (21). The cDNA encoding Flag-Ets-1 was cloned into pLV-CAG-EGFP vector (kindly provided by Dr. Masahito Ikawa, Osaka University, Osaka, Japan).…”

Section: Plasmids and Luciferase Reporter Assaysmentioning

confidence: 99%

Interaction of Ets-1 with HDAC1 Represses IL-10 Expression in Th1 Cells

Lee

Kwon

Sahoo

et al. 2012

The Journal of Immunology

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IL-10 is a multifunctional cytokine that plays a crucial role in immunity and tolerance. IL-10 is produced by diverse immune cell types, including B cells and subsets of T cells. Although Th1 produce IL-10, their expression levels are much lower than Th2 cells under conventional stimulation conditions. The potential role of E26 transformation-specific 1 (Ets-1) transcription factor as a negative regulator for Il10 gene expression in CD4+ T cells has been implicated previously. In this study, we investigated the underlying mechanism of Ets-1–mediated Il10 gene repression in Th1 cells. Compared with wild type Th1 cells, Ets-1 knockout Th1 cells expressed a significantly higher level of IL-10, which is comparable with that of wild type Th2 cells. Upregulation of IL-10 expression in Ets-1 knockout Th1 cells was accompanied by enhanced chromatin accessibility and increased recruitment of histone H3 acetylation at the Il10 regulatory regions. Reciprocally, Ets-1 deficiency significantly decreased histone deacetylase 1 (HDAC1) enrichment at the Il10 regulatory regions. Treatment with trichostatin A, an inhibitor of HDAC family, significantly increased Il10 gene expression by increasing histone H3 acetylation recruitment. We further demonstrated a physical interaction between Ets-1 and HDAC1. Coexpression of Ets-1 with HDAC1 synergistically repressed IL-10 transcription activity. In summary, our data suggest that an interaction of Ets-1 with HDAC1 represses the Il10 gene expression in Th1 cells.

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Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses

Cited by 118 publications

References 54 publications

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Interaction of Ets-1 with HDAC1 Represses IL-10 Expression in Th1 Cells

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