scholarly journals Chemical epigenetics to assess the role of HDAC1–3 inhibition in macrophage pro-inflammatory gene expression

MedChemComm ◽  
2016 ◽  
Vol 7 (11) ◽  
pp. 2184-2190 ◽  
Author(s):  
Maria E. Ourailidou ◽  
Niek G. J. Leus ◽  
Kim Krist ◽  
Alessia Lenoci ◽  
Antonello Mai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Gene Expression ◽  
Murine Macrophages ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Azobenzene ortho-aminoanilides inhibit HDACs 1–3 and possess anti-inflammatory properties in murine macrophages.

scholarly journals Effect of PGC-1αon Proliferation, Migration, and Transdifferentiation of Rat Vascular Smooth Muscle Cells Induced by High Glucose

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaoqiang Qi ◽  
Yujing Zhang ◽  
Jing Li ◽  
Dongxia Hou ◽  
Yang Xiang
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Glucose ◽  
Muscle Cells ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

We assessed the role of PGC-1α (PPARγ coactivator-1 alpha) in glucose-induced proliferation, migration, and inflammatory gene expression of vascular smooth muscle cells (VSMCs). We carried out phagocytosis studies to assess the role of PGC-1α in transdifferentiation of VSMCs by flow cytometry. We found that high glucose stimulated proliferation, migration and inflammatory gene expression of VSMCs, but overexpression of PGC-1α attenuated the effects of glucose. In addition, overexpression of PGC-1α decreased mRNA and protein level of VSMCs-related genes, and induced macrophage-related gene expression, as well as phagocytosis of VSMCs. Therefore, PGC-1α inhibited glucose-induced proliferation, migration and inflammatory gene expression of VSMCs, which are key features in the pathology of atherosclerosis. More importantly, PGC-1α transdifferentiated VSMCs to a macrophage-like state. Such transdifferentiation possibly increased the portion of VSMCs-derived foam cells in the plaque and favored plaque stability.

scholarly journals SETD1 and NF-κB Regulate Periodontal Inflammation through H3K4 Trimethylation

2020 ◽  
Vol 99 (13) ◽  
pp. 1486-1493 ◽  
Author(s):  
M. Francis ◽  
G. Gopinathan ◽  
A. Salapatas ◽  
S. Nares ◽  
M. Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Methylation ◽  
Gene Promoters ◽  
Cell Culture Model ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
H3k4 Trimethylation ◽  
Periodontal Inflammation ◽  
Culture Model

The inflammatory response to periodontal pathogens is dynamically controlled by the chromatin state on inflammatory gene promoters. In the present study, we have focused on the effect of the methyltransferase SETD1B on histone H3 lysine K4 (H3K4) histone trimethylation on inflammatory gene promoters. Experiments were based on 3 model systems: 1) an in vitro periodontal ligament (PDL) cell culture model for the study of SETD1 function as it relates to histone methylation and inflammatory gene expression using Porphyromonas gingivalis lipopolysaccharide (LPS) as a pathogen, 2) a subcutaneous implantation model to determine the relationship between SETD1 and nuclear factor κB (NF-κB) through its activation inhibitor BOT-64, and 3) a mouse periodontitis model to test whether the NF-κB activation inhibitor BOT-64 reverses the inflammatory tissue destruction associated with periodontal disease. In our PDL progenitor cell culture model, P. gingivalis LPS increased H3K4me3 histone methylation on IL-1β, IL-6, and MMP2 gene promoters, while SETD1B inhibition decreased H3K4me3 enrichment and inflammatory gene expression in LPS-treated PDL cells. LPS also increased SETD1 nuclear localization in a p65-dependent fashion and the nuclear translocation of p65 as mediated through SETD1, suggestive of a synergistic effect between SETD1 and p65 in the modulation of inflammation. Confirming the role of SETD1 in p65-mediated periodontal inflammation, BOT-64 reduced the number of SETD1-positive cells in inflamed periodontal tissues, restored periodontal tissue integrity, and enhanced osteogenesis in a periodontal inflammation model in vivo. Together, these results have established the histone lysine methyltransferase SETD1 as a key factor in the opening of the chromatin on inflammatory gene promoters through histone H3K4 trimethylation. Our studies also confirmed the role of BOT-64 as a potent molecular therapeutic for the restoration of periodontal health through the inhibition of NF-κB activity and the amelioration of SETD1-induced chromatin relaxation.

P151 DISRUPTION OF ENDOGENOUS ITACONATE PRODUCTION EXACERBATES EXPERIMENTAL COLITIS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S5-S6
Author(s):  
Ryan Frieler ◽  
Thomas Vigil ◽  
Richard Mortensen ◽  
Yatrik Shah
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Tricarboxylic Acid Cycle ◽  
Myeloid Cells ◽  
Experimental Colitis ◽  
Cell Types ◽  
Cell Phenotype ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Abstract Background Inflammation is a hallmark of inflammatory bowel disease and alterations in tricarboxylic acid cycle (TCA) metabolism have been identified as major regulators of immune cell phenotype during inflammation and hypoxia. The TCA cycle metabolite, itaconate, is produced by the enzyme aconitate decarboxylase 1 (Acod1) and is highly upregulated during classical macrophage activation and during experimental colitis. Itaconate and cell permeable derivatives have robust anti-inflammatory effects on macrophages, therefore we hypothesized that Acod1-produced itaconate has a protective, anti-inflammatory effect during experimental colitis. Methods and Results Wild type (WT) control and Acod1-/- mice were administered 3% Dextran Sulfate Sodium (DSS) in water for 7 days to induce experimental colitis. After DSS was discontinued, Acod1-/- mice had significantly reduced body weight recovery with increased macroscopic disease severity, and upon dissection had decreased colon length and more severe inflammation. To determine if myeloid cells are the critical Acod1/itaconate-producing cell types, we generated myeloid-specific Acod1 deficient mice, however no differences in weight loss, colon length or inflammatory gene expression were detected compared to WT controls. To test whether supplementation with exogenous itaconate could ameliorate colitis, WT mice were treated with the cell-permeable form of itaconate, dimethyl itaconate (DMI). Administration of DMI significantly improved recovery after 7 days of DSS treatment and significantly reduced inflammatory gene expression in the colon. Conclusion Our data suggest that Acod1-produced itaconate has an important role in the regulation of inflammation during experimental colitis. Although myeloid cells have been thought to be major producers of Acod1 and itaconate, our data indicate that other cell types are involved. These results highlight the importance of this immunometabolic pathway and suggest that preservation or enhancement of this pathway with natural metabolites or metabolite derivatives could have beneficial effects during colitis.

scholarly journals Anti-Inflammatory Effects of HDL (High-Density Lipoprotein) in Macrophages Predominate Over Proinflammatory Effects in Atherosclerotic Plaques

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Panagiotis Fotakis ◽  
Vishal Kothari ◽  
David G. Thomas ◽  
Marit Westerterp ◽  
Matthew M. Molusky ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Density ◽  
Mitogen Activated Protein Kinase ◽  
Endoplasmic Reticulum Stress Response ◽  
Cholesterol Depletion ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Objective: HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects of HDL in macrophages, and there is no consensus on the underlying mechanisms. Here, we interrogate the effects of HDL on inflammatory gene expression in macrophages. Approach and Results: We cultured bone marrow–derived macrophages, treated them with reconstituted HDL or HDL isolated from APOA1 Tg ;Ldlr −/− mice, and challenged them with lipopolysaccharide. Transcriptional profiling showed that HDL exerts a broad anti-inflammatory effect on lipopolysaccharide-induced genes and proinflammatory effect in a subset of genes enriched for chemokines. Cholesterol removal by POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) liposomes or β-methylcyclodextrin mimicked both pro- and anti-inflammatory effects of HDL, whereas cholesterol loading by POPC/cholesterol-liposomes or acetylated LDL (low-density lipoprotein) before HDL attenuated these effects, indicating that these responses are mediated by cholesterol efflux. While early anti-inflammatory effects reflect reduced TLR (Toll-like receptor) 4 levels, late anti-inflammatory effects are due to reduced IFN (interferon) receptor signaling. Proinflammatory effects occur late and represent a modified endoplasmic reticulum stress response, mediated by IRE1a (inositol-requiring enzyme 1a)/ASK1 (apoptosis signal-regulating kinase 1)/p38 MAPK (p38 mitogen-activated protein kinase) signaling, that occurs under conditions of extreme cholesterol depletion. To investigate the effects of HDL on inflammatory gene expression in myeloid cells in atherosclerotic lesions, we injected reconstituted HDL into Apoe −/− or Ldlr −/− mice fed a Western-type diet. Reconstituted HDL infusions produced anti-inflammatory effects in lesion macrophages without any evidence of proinflammatory effects. Conclusions: Reconstituted HDL infusions in hypercholesterolemic atherosclerotic mice produced anti-inflammatory effects in lesion macrophages suggesting a beneficial therapeutic effect of HDL in vivo.

123. Response and habituation of pro- and anti-inflammatory gene expression to repeated psychosocial stress

2014 ◽  
Vol 40 ◽  
pp. e36
Author(s):  
C. McInnis ◽  
M. Thoma ◽  
D. Gianferante ◽  
L. Hanlin ◽  
X. Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Psychosocial Stress ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Anti Inflammatory
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