SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide-induced inflammatory cytokines in macrophages

Chang, Cheng; Huang, Cheng; Ma, Tao; Bian, Erbao; He, Yong; Zhang, Lei; Li, Jun

doi:10.1016/j.toxlet.2013.12.023

Cited by 96 publications

(82 citation statements)

References 56 publications

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“…Moreover, the SOCS1 gene was significantly elevated in both tumorinfiltrating DCs and BM-TADCs, which could be attributable to the hypomethylation caused by DNMT1 reduction. Previous study reported that DNMT1-mediated SOCS1 hypermethylation enhanced LPS-triggered cytokine production in macrophages (48). Our data in this work suggest that DNMT1-mediated SOCS1 hypermethylation and gene silencing are essential for maintaining the responsiveness of DCs to TLR stimulation.…”

Section: Discussionsupporting

confidence: 64%

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis

Liu

et al. 2016

The Journal of Immunology

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Immunosuppressive tumor-associated dendritic cells (TADCs) are potential targets for cancer therapy. However, their poor responsiveness to TLR stimulation is a major obstacle for achieving successful cancer immunotherapy. In the current study, we reported a dysregulated miR-148a/DNA methyltransferase (DNMT)1/suppressor of cytokine signaling (SOCS)1 axis as a unique mechanism for dampened TLR stimulation in TADCs. The results showed that aberrantly elevated miR-148a in bone marrow–derived TADC (BM-TADC) abolished polyinosinic-polycytidylic acid (poly I:C) or LPS-induced dendritic cell maturation through directly suppressing DNMT1 gene, which consequently led to the hypomethylation and upregulation of SOCS1, the suppressor of TLR signaling. In contrast, miR-148a inhibitor (miR-148ai) effectively rescued the expression of DNMT1 and decreased SOCS1 in BM-TADCs, thereby recovering their sensitivity to TLR3 or TLR4 stimulation. To further reprogram TADCs in vivo, miR-148ai was coencapsulated with poly I:C and OVA by cationic polypeptide micelles to generate integrated polypeptide micelle/poly I:C (PMP)/OVA/148ai nanovaccine, which was designed to simultaneously inhibit miR-148a and activate TLR3 signaling in TADCs. The immunization of PMP/OVA/148ai nanovaccine not only effectively modulated the miR-148a/DNMT1/SOCS1 axis in the spleen, but also significantly increased mature dendritic cells both in the spleen and in tumor microenvironment. Moreover, PMP/OVA/148ai ameliorated tumor immunosuppression through reducing regulatory T cells and myeloid-derived suppressor cells, thereby leading to potent anticancer immune responses and robust tumor regression with prolonged survival. This study proposes a nanovaccine-based immunogene therapy with the integration of miR-148a inhibition and TLR3 stimulation as a novel therapeutic approach to boost anticancer immunity by reprogramming TADCs in vivo.

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Section: Discussionsupporting

confidence: 64%

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis

Liu

et al. 2016

The Journal of Immunology

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“…Another DNMT, DNMT1 is also associated with the release of proinflammatory cytokines in macrophages by hypermethylating Suppressor of cytokine signaling 1 (SOCS1). Inhibition of DNMT1 downregulates the activation of the Janus kinase (JAK)-2/STAT3 pathway in RAW264.7 cells after LPS induction and thereby prevents the inflammatory phenotype [99]. These examples provide clear evidence that inhibition of demethylases modulates the transcriptional activation of genes for M2 macrophages and drugs that target DNMTs could be used to promote anti-inflammatory responses to reduce inflammation.…”

Section: Epigenetic Modifiers and Macrophage Polarizationmentioning

confidence: 99%

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

Patel

Rajasingh

Samanta

et al. 2017

Drug Discovery Today

170

115

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Macrophages are a heterogeneous population of phagocytic cells present in all tissues. Recently, several drugs that target the epigenetic machinery have emerged as attractive molecules for treating infection and inflammation by modulating macrophages. Treatment of lipopolysaccharide (LPS)-challenged macrophages with epigenetic modifiers leads to phenotype switching. This could provide stimulatory/destructive (M1) or suppressive/protective (M2) therapeutic strategies, which are crucial in the cytokine milieu in which the macrophages reside. In this review, we provide an overview of macrophage functional diversity during various diseases, including infection, as well as the current status in the development and clinical utility of epigenetic modifiers.

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“…In line with this, SOCS1 knockout or knockdown M1-activated macrophages show enhanced levels of IL-6, IL-12, MHC class II, and nitric oxide suggesting SOCS1 sustains the properties of M1 macrophages at a less destructive level to prevent overshooting inflammatory responses (4, 18). This explains why SOCS1 promoter hypermethylation, which results in loss of SOCS1 expression leads to enhanced secretion of lipopolysaccharide (LPS)-induced pro-inflammatory cytokines (20). Micro RNA-155 (miR-155) is a critical regulator of innate immunity and TLR signaling (21–23); miR-155 targets and degrades SOCS1 in M1-activated macrophages (21), thus miR-155 induction during activation serves to maximize and extend the inflammatory process.…”

Section: Socs Proteinsmentioning

confidence: 99%

SOCS Proteins in Macrophage Polarization and Function

2014

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SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide-induced inflammatory cytokines in macrophages

Cited by 96 publications

References 56 publications

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

SOCS Proteins in Macrophage Polarization and Function

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