DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Abstract

The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor–mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.

Comparing the role of Ginkgolide B and Ginkgolide K on cultured astrocytes exposed to oxygen‑glucose deprivation

“…In this study, GK treatment inhibited the expression of p-NF-κB/p65 and upregulated the Nrf2 pathway, indicating potential complicated crosstalk between NF-κB and Nrf2, which may contribute to the improvement in the inflammatory microenvironment of the brain and promote neuroprotection and nerve regeneration. In this study, the inhibition of NF-κB and TNF-α in OGD astrocytes treated with GK might be related to the increased expression of IL-10 ( 41 – 43 ). Additionally, a series of studies have demonstrated that the activation and nuclear translocation of Nrf2 and the expression of various antioxidant enzymes can be mediated via the PI3K/Akt pathway ( 44 , 45 ).…”

TET2- and TDG-mediated changes are required for the acquisition of distinct histone modifications in divergent terminal differentiation of myeloid cells

“…GO analysis identified significant enrichment in functions related to OC biology, ( Supplementary Figure S2B , right) and HOMER analysis revealed putative TF binding motifs such as Jun/Fos, BATF or ZNF528 ( Supplementary Figure S2C ). These small 5mC changes across cell differentiation affected genes involved in proteolytic activity ( CTSK, ADAMTS8, HYAL2 ) and related with NF-κB regulation ( URGCP and WDFY1 as activators and ZNF366, SLC39A1 and CUX1 as inhibitors) ( 35 – 37 ). Bisulfite pyrosequencing of representative CpGs ( CTSK and ZNF366 ) confirmed their demethylation in OCs, but also some partial demethylation in MACs ( Supplementary Figure S2D ), suggesting that the observed differences may be indirect rather than the result of specific targeting by elements downstream of RANKL.…”

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

“…Since activation of tolDCs has been shown to increase lymph node homing, antigen presentation, and stability against other inflammatory modulators ( 32 ), we activated Dex-treated DCs with MPLA (DM-DCs), a non-toxic clinical grade analog of LPS, which also signals via toll-like receptor 4 and exhibits potent immune-stimulatory capacity ( 33 , 34 ). Glucocorticoid receptors are transcription factors that suppress the pro-inflammatory program induced by TLRs and in turn potentiate TLR-mediated anti-inflammatory responses such as IL-10 secretion ( 35 , 36 ). Our group has previously shown that Dex and MPLA induce a tolerogenic profile in moDCs from both healthy controls and RA patients ( 21 , 22 ).…”