scholarly journals Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay

2011 ◽  
Vol 71 (3) ◽  
pp. 424-431 ◽  
Author(s):  
Aleksander M Grabiec ◽  
Olexandr Korchynskyi ◽  
Paul P Tak ◽  
Kris A Reedquist
Keyword(s):  
Rheumatoid Arthritis ◽  
Histone Deacetylase ◽  
Inflammatory Cytokine ◽  
Mrna Decay ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Trichostatin A ◽  
Binding Activity ◽  
Inflammatory Cytokine Production

BackgroundHistone deacetylase inhibitors (HDACi) display potent therapeutic efficacy in animal models of arthritis and suppress inflammatory cytokine production in rheumatoid arthritis (RA) synovial macrophages and tissue.ObjectivesTo determine the molecular mechanisms contributing to the suppressive effects of HDACi on RA synovial cell activation, using interleukin 6 (IL-6) regulation as a model.MethodsRA fibroblast-like synoviocytes (FLS) and healthy donor macrophages were treated with IL-1β, tumour necrosis factor (TNF)α, lipopolysaccharide or polyinosinic:polycytidylic acid (poly(I:C)) in the absence or presence of the HDACi trichostatin A (TSA) or ITF2357 (givinostat). IL-6 production and mRNA expression was measured by ELISA and quantitative PCR (qPCR), respectively. Protein acetylation and the activation of intracellular signalling pathways were assessed by immunoblotting. The DNA-binding activity of nuclear factor κB (NFκB) and activator protein 1 (AP-1) components was measured by ELISA-based assays.ResultsHDACi (0.25–1.0 μM) suppressed RA FLS IL-6 production induced by IL-1β, TNFα and Toll-like receptor ligands. Phosphorylation of mitogen-activated protein kinases and inhibitor of κBα (IκBα) following IL-1β stimulation were unaffected by HDACi, as were AP-1 composition and binding activity, and c-Jun induction. TSA induced a significant reduction in nuclear retention of NFκB in FLS 24 h after IL-1β stimulation, but this did not reduce NFκB transcriptional activity or correlate temporally with reductions in IL-6 mRNA accumulation. HDACi significantly reduced the stability of IL-6 mRNA in FLS and macrophages.ConclusionsOur study identifies a novel, shared molecular mechanism by which HDACi can disrupt inflammatory cytokine production in RA synovial cells, namely the promotion of mRNA decay, and suggests that targeting HDAC activity may be clinically useful in suppressing inflammation in RA.

scholarly journals Trimetazidine protects retinal ganglion cells from acute glaucoma via the Nrf2/Ho-1 pathway

2017 ◽  
Vol 131 (18) ◽  
pp. 2363-2375 ◽  
Author(s):  
Peixing Wan ◽  
Wenru Su ◽  
Yingying Zhang ◽  
Zhidong Li ◽  
Caibin Deng ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Retinal Ganglion ◽  
Inflammatory Cytokine Production ◽  
Acute Glaucoma

Acute glaucoma is one of the leading causes of irreversible vision impairment characterized by the rapid elevation of intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Oxidative stress and neuroinflammation have been considered critical for the pathogenesis of RGC death in acute glaucoma. Trimetazidine (TMZ), an anti-ischemic drug, possesses antioxidative and anti-inflammatory properties, contributing to its therapeutic potential in tissue damage. However, the role of TMZ in acute glaucoma and the underlying molecular mechanisms remain elusive. Here, we report that treatment with TMZ significantly attenuated retinal damage and RGC death in mice with acute glaucoma, with a significant decrease in reactive oxygen species (ROS) and inflammatory cytokine production in the retina. Furthermore, TMZ treatment directly decreased ROS production and rebalanced the intracellular redox state, thus contributing to the survival of RGCs in vitro. TMZ treatment also reduced the production of inflammatory cytokines in vitro. Mechanistically, the TMZ-mediated inhibition of apoptosis and inflammatory cytokine production in RGCs occurred via the regulation of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1/caspase-8 pathway. Moreover, the TMZ-mediated neuroprotection in acute glaucoma was abrogated when an HO-1 inhibitor, SnPP, was used. Our findings identify potential mechanisms of RGC apoptosis and propose a novel therapeutic agent, TMZ, which exerts a precise neuroprotective effect against acute glaucoma.

scholarly journals Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production

2014 ◽  
Vol 25 (21) ◽  
pp. 3300-3307 ◽  
Author(s):  
Bin Wang ◽  
Ting-yu Liu ◽  
Chun-Hsiang Lai ◽  
Yan-hua Rao ◽  
Moon-Chang Choi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Response ◽  
Histone Deacetylase ◽  
Inflammatory Cytokine ◽  
Caspase 3 ◽  
Cytokine Production ◽  
Metabolic Reprogramming ◽  
Inflammatory Cytokine Production ◽  
Histone Deacetylase 4 ◽  
Lps Treatment

Activation of the inflammatory response is accompanied by a metabolic shift to aerobic glycolysis. Here we identify histone deacetylase 4 (HDAC4) as a new component of the immunometabolic program. We show that HDAC4 is required for efficient inflammatory cytokine production activated by lipopolysaccharide (LPS). Surprisingly, prolonged LPS treatment leads to HDAC4 degradation. LPS-induced HDAC4 degradation requires active glycolysis controlled by GSK3β and inducible nitric oxide synthase (iNOS). Inhibition of GSK3β or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation. We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation. Of importance, a caspase-3–resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production. Our findings identify the GSK3β-iNOS-NO axis as a critical signaling cascade that couples inflammation to metabolic reprogramming and a glycolysis-driven negative feedback mechanism that limits inflammatory response by triggering HDAC4 degradation.

scholarly journals Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

2017 ◽  
Author(s):  
Erin T. Larragoite ◽  
Laura J. Martins ◽  
Adam M. Spivak ◽  
Racheal A. Nell ◽  
Vicente Planelles
Keyword(s):  
Histone Deacetylase ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Viral Reactivation ◽  
Inflammatory Cytokine Production ◽  
Epigenetic Modifier ◽  
Hiv 1 ◽  
Pro Inflammatory Cytokines

AbstractIntroductionThough antiretroviral therapy has led to viral suppression and increased quality of life for patients living with HIV-1, strategies to eliminate the HIV-1 latent reservoir are still necessary to eliminate HIV. Latency reversal with superior latency reversal agents (LRAs) such as protein kinase C (PKC) agonists is a promising strategy for unveiling and eliminating the latent HIV-1 reservoir. However, PKC agonists induce T cell activation and deleterious pro- inflammatory cytokine production. Secondary pharmacological agents combined with LRAs have been previously shown to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 viral reactivation. Histone deacetylase inhibitors (HDACi) are also known for inhibiting deleterious pro-inflammatory cytokines in the context of graft-versus-host disease and rheumatoid arthritis in addition to being known to synergize with PKC agonists. In this study we investigated whether HDACi and other epigenetic modifiers could decrease PKC- induced pro-inflammatory cytokines secretion while simultaneously synergizing with the PKC agonists Ingenol-3,20-dibenzoate, to enhance latency reversal.MethodsWe screened an epigenetic modifier library in health donor human peripheral blood mononuclear cells (PBMCs) to identify compounds (‘hits’) that reduced intracellular IL-6 pro-inflammatory cytokine production induced by PKC agonist Ingenol-3,20-dibenzoate. We then further tested reducers of intracellular IL-6 (‘hits’) for their ability to synergize with Ingenol-3,20-dibenzoate in the J-LAT 10.6 model of HIV-1 latency. The most promising epigenetic modifier from both screens, the HDACi Panobinostat, was then further tested for its ability to reduce pro-inflammatory cytokines and synergize with Ingenol-3,20-dibenzoate.ResultsWe show that co-treatment with Ingenol-3,20-dibenzoate and Panobinostat reduces pro-inflammatory cytokines and enhances latency reversal in vitro. Panobinostat suppressed pro-inflammatory cytokine production when combined with Ingenol-3,20- dibenzoate ex vivo when using aviremic patient cells, but antagonized Ingenol-3,20-dibenzoate dependent latency reversal ex vivo.ConclusionThe combination of Panobinostat and Ingenol-3,20-dibenzoate reduces deleterious cytokine production but is not a suitable latency reversal combination therapy.

Ginsenoside Rb1 alleviates lipopolysaccharide-induced inflammatory injury by downregulating miR-222 in WI-38 cells

2020 ◽  
Author(s):  
Erhu Wei ◽  
Xiao Fang ◽  
Peisheng Jia ◽  
Mingxia Li ◽  
Peina Jin ◽  
...  
Keyword(s):  
Cell Viability ◽  
Inflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Panax Notoginseng ◽  
Lung Fibroblasts ◽  
Ginsenoside Rb1 ◽  
Inflammatory Cytokine Production ◽  
Inflammatory Injury ◽  
Factor Α

Abstract Background Pneumonia is a serious respiratory tract infection disease in children, which threatens to the health or life of children patients. Ginsenoside Rb1 (Rb1) is a principle active ingredient extracted from the root of Panax notoginseng (Burk.) F.H.Chen with anti-inflammatory effect. Our study aimed to determine the effects and molecular mechanisms of Rb1 on lipopolysaccharide (LPS)-induced inflammatory injury of lung fibroblasts WI-38 cells. Methods Cell viability and apoptosis were evaluated by CCK-8 and flow cytometry analysis, respectively. The production of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-lβ, and IL-6 were measured by ELISA and RT-qPCR. miR-222 expression was examined by RT-qPCR. The expression levels of the nuclear factor-kappa B (NF-κB) p65 and phosphorylated p65 were detected by western blot. Results LPS stimulation induced WI-38 cell inflammatory injury by inhibiting cell viability, and inducing apoptosis and inflammatory cytokine production, while treatment with Rb1 significantly attenuated LPS-induced inflammatory injury in WI-38 cells. Additionally, Rb1 decreased LPS-induced upregulation of miR-222 and activation of the NF-κB pathway in WI-38 cells. Overexpression of miR-222 abolished the inhibitory effects of Rb1 on LPS-induced viability reduction, apoptosis, inflammatory cytokine production and activation of the NF-κB pathway. Conclusion Rb1 alleviated LPS-induced inflammatory injury in WI-38 cells via downregulating miR-222 and inactivation of the NF-κB pathway, contributing to our understanding of the effects and molecular mechanism of Rb1 in pneumonia.

Sign in / Sign up

Export Citation Format

Share Document