New Insights into the Role of Histone Deacetylases as Coactivators of Inflammatory Gene Expression

2015 ◽  
Vol 23 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Michael Lienhard Schmitz ◽  
Laureano de la Vega
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

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.

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 The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

2016 ◽  
Vol 102 ◽  
pp. 130-140 ◽  
Author(s):  
Thea van den Bosch ◽  
Alexander Boichenko ◽  
Niek G.J. Leus ◽  
Maria E. Ourailidou ◽  
Hannah Wapenaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Histone Acetyltransferase ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Acetyltransferase P300

scholarly journals Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators

2014 ◽  
Vol 40 ◽  
pp. 96-107 ◽  
Author(s):  
Perla Kaliman ◽  
María Jesús Álvarez-López ◽  
Marta Cosín-Tomás ◽  
Melissa A. Rosenkranz ◽  
Antoine Lutz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Rapid Changes

scholarly journals Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77

2006 ◽  
Vol 20 (4) ◽  
pp. 786-794 ◽  
Author(s):  
Liming Pei ◽  
Antonio Castrillo ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Liver X Receptor ◽  
Nuclear Hormone Receptor ◽  
Orphan Nuclear Receptor ◽  
Orphan Nuclear Receptors ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

Abstract Members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression in inflammation and disease. Previous studies have shown that the lipid-activated receptors peroxisomal proliferator-activated receptor and liver X receptor inhibit nuclear factor-κB (NF-κB) signaling and inflammatory gene expression. We recently identified the NR4A subfamily of orphan nuclear receptors (Nur77/NR4A1, Nurr1/NR4A2, and NOR1/NR4A3) as lipopolysaccharide- and NF-κB-responsive genes in macrophages. However, the role of these transcription factors in macrophage gene expression is unknown. We demonstrate here that, in contrast to peroxisomal proliferator-activated receptor and liver X receptor, the role of NR4A receptors in macrophages is proinflammatory. Retroviral expression of Nur77 in macrophages leads to the transcriptional activation of multiple genes involved in inflammation, apoptosis, and cell cycle control. One particularly interesting Nur77-responsive gene is the inducible kinase IKKi/IKKε, an important component of the NF-κB signaling pathway. The IKKi promoter contains a functional NR4A binding site and is activated by all three NR4A receptors in transient transfection assays. Consistent with the activation of IKKi, expression of Nur77 in macrophages potentiates the induction of inflammatory gene expression in response to lipopolysaccharide. These results identify a new role for NR4A orphan nuclear receptors in the control of macrophage gene expression during inflammation.

scholarly journals Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex

2019 ◽  
Vol 40 (5) ◽  
pp. 1117-1131 ◽  
Author(s):  
Tsubasa Takizawa ◽  
Tao Qin ◽  
Andreia Lopes de Morais ◽  
Kazutaka Sugimoto ◽  
Joon Yong Chung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Tnf Α ◽  
Inflammatory Processes ◽  
Factor Α ◽  
The Relationship

Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.

scholarly journals HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

2019 ◽  
Vol 99 (1) ◽  
pp. 98-106 ◽  
Author(s):  
K.B. Lagosz ◽  
A. Bysiek ◽  
J.M. Macina ◽  
G.P. Bereta ◽  
M. Kantorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Mediators ◽  
Histone Deacetylases ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Gingival Fibroblast ◽  
Mrna Levels ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Inflammatory Activation

Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis–inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs ( IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis–infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis–induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

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