TonEBP suppresses IL-10-mediated immunomodulation

Choi, Soo Youn; Lee, Hwan Hee; Lee, Jun Ho; Ye, Byeong Jin; Yoo, Eun Jin; Kang, Hye-Won; Jung, Gyu Won; An, Seung Min; Lee-Kwon, Whaseon; Chiong, Mario; Lavandero, Sergio; Kwon, Hyug Moo

doi:10.1038/srep25726

Cited by 25 publications

(31 citation statements)

References 56 publications

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“…(33), NFAT5 also modulated their response to the polarizing cytokines IFN-g and IL-4. Our findings showing that NFAT5 could promote the expression of various IL-4-responsive genes in primary macrophages differed from those in a recent report using the cell line RAW264.7, in which NFAT5 repressed the expression of arginase 1, IL-10, and MRC1/CD206 induced by IL-4 (41). As experiments by Choi et al only achieved partial downregulation of NFAT5 with small interfering RNA in the cell line RAW264.7, it is possible that they might have missed relevant differences that we have identified in this study using primary macrophages with a complete deletion of NFAT5.…”

Section: Nfat5 Regulates Different Genes In Macrophages Polarized Witcontrasting

confidence: 57%

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

Tellechea

Buxadé

Tejedor

et al. 2018

The Journal of Immunology

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Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions.

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Section: Nfat5 Regulates Different Genes In Macrophages Polarized Witcontrasting

confidence: 57%

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

Tellechea

Buxadé

Tejedor

et al. 2018

The Journal of Immunology

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“…Besides, NF-kB was also known to interact with BRD4 in other cells ( 29 ). Based to these, we designed three sites for IL-10 DNA regulatory regions covering the hyper sensitive site (HSS, upstream 4.5 kb) ( 30 ), distal promoter (DP, upstream 1.2 kb), and proximal promoter (PP, upstream 0.2 kb) ( 31 , 32 ) which are known as functional DNA elements for IL-10 transcription ( Fig. 4A ).…”

Section: Resultsmentioning

confidence: 99%

JQ1, a BET inhibitor, controls TLR4-induced IL-10 production in regulatory B cells by BRD4-NF-κB axis

Lee

Hong

et al. 2017

BMB Rep.

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Regulatory B cells, also well-known as IL-10-producing B cells, play a role in the suppression of inflammatory responses. However, the epigenetic modulation of regulatory B cells is largely unknown. Recent studies showed that the bromodomain and extra-terminal domain (BET) protein inhibitor JQ1 controls the expression of various genes involving cell proliferation and cell cycle. However, the role of BET proteins on development of regulatory B cells is not reported. In this study, JQ1 potently suppressed IL-10 expression and secretion in murine splenic and peritoneal B cells. While bromodomain-containing protein 4 (BRD4) was associated with NF-κB on IL-10 promoter region by LPS stimulation, JQ1 interfered the interaction of BRD4 with NF-κB on IL-10 promoter. In summary, BRD4 is essential for toll like receptor 4 (TLR4)-mediated IL-10 expression, suggesting JQ1 could be a potential candidate in regulating IL-10-producing regulatory B cells in cancer.

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“…Data in the previous sections demonstrate the relevance of TonEBP to glycemic stress-induced inflammation, renal function, and BP. Moreover, previously published associations of TonEBP expression with inflammation, 6,22 rheumatoid arthritis, 7,8 atherosclerosis, 9 and DN in humans 10 raised the possibility that variations in TonEBP might affect similar phenotypes in humans. Accordingly, we performed a look-up of TonEBP variant association in a highly homogeneous cohort of healthy individuals with minimal confounders (see Methods and Supplemental Material for details) with measures of inflammation, renal function, and BP.…”

Section: Association Of Tonebp Polymorphisms With Inflammatory Vascumentioning

confidence: 99%

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Choi

Lim

Salimi

et al. 2018

JASN

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Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.

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TonEBP suppresses IL-10-mediated immunomodulation

Cited by 25 publications

References 56 publications

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

JQ1, a BET inhibitor, controls TLR4-induced IL-10 production in regulatory B cells by BRD4-NF-κB axis

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

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