The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages

Abstract

Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.

High SET Domain Bifurcated 1 (SETDB1) Expression Predicts Poor Prognosis in Breast Carcinoma

“…Our results suggest that specific knockdown of SETDB1 induced the expression of IL-6. In line with the above phenomena, Hachiva et al reported Setdb1 induced TLR4mediated IL-6 expression in macrophages and macrophagespecific knockout mice [25], suggesting SETDB1 is involved in IL-6 transcription and the inflammatory response in BC. Except for IL-6, the other 9 hub genes have not been shown to be linked to SETDB1.…”

“…Consistent with these results, Adoue et al demonstrated that SETDB1 resulted in H3K9me3 deposition at a cell-type-specific set and ensured Th cell lineage integrity by inhibiting a repertoire of endogenous retroviruses [24]. Moreover, a recent observation showed that SEDB1 significantly prevented the expression of the proinflammatory cytokine (IL-6) through its methyltransferase activity in macrophages, and macrophage-specific Setdb1-knockout mice had higher serum interleukin-6 concentrations [25]. Additionally, the knockdown of SETDB1 interfered with the interaction between PIWIL4 and HP1 proteins, indicating SETDB1 is important for the differentiation e922982-8 of monocytes [26].…”

SETDB1 promotes glioblastoma growth via CSF-1 - dependent macrophage recruitment by activating the AKT/mTOR signaling pathway

“…Research has identi ed the overexpression of SETDB1 in many malignancies, such as glioblastoma, melanoma, prostate cancer, and breast cancer (BRC), which was linked to cancer cell division as well as metastasis [23,26,38]. Previously study have shown that SETDB1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proin ammatory cytokines including interleukin-6 through its methyltransferase activity [40]. However, a complete picture is lacking in this area of cancer studies.…”

Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

“…However, TLR2 expression is dramatically increased upon stimulation with inflammatory factors. In contrast to TLR4, which potentiates macrophage responses during inflammation [33], TLR2 is expressed more broadly in vascular cells and promotes endothelial dysfunction [34]. To further characterize the relationship between TLR2 and chemerin, we knocked down TLR2 and TLR4 of HUVECs with shRNA.…”