Simvastatin Inhibits Toll-like Receptor 8 (TLR8) Signaling in Primary Human Monocytes and Spontaneous Tumor Necrosis Factor Production from Rheumatoid Synovial Membrane Cultures

Mullen, Lisa; Ferdjani, Jason K; Sacre, Sandra

doi:10.2119/molmed.2015.00154

Cited by 11 publications

(13 citation statements)

References 47 publications

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“…Indeed, this inflammatory mediator is one of the detrimental factors for disease progression as it stimulates osteoclast activity by inducing RANKL production, in addition to MMP production 17,21. Simvastatin was previously suggested to inhibit TNF-α 12. This study found that simvastatin does not affect TNF-α production at 14 days after disease induction, as animals treated with this drug exhibited similar levels of this mediator in their gingival samples to those of the vehicle-treated group.…”

Section: Discussionmentioning

confidence: 60%

“…Recently, an anti-inflammatory effect was suggested for antihypertensive drugs (angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, β-blockers) in periodontitis 8,9. More recently, the cholesterol-lowering drug simvastatin, used as adjuvant in hypertensive patients with dyslipidemia, was suggested to have a protective effect against experimental10,11 and human periodontitis 9,12. This effect was attributed to its capacity to reduce bone loss and modulate the expression/release of inflammatory markers in gingival crevicular fluid samples.…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis

Júnior¹,

Macedo²,

Abdalla³

et al. 2017

CCIDE

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PurposeThe aim of this study was to evaluate the effect of simvastatin on the synthesis of cytokines TNF-α and IL-10 and metalloproteinase (MMPs) 2 and 9 in a rat model of ligature-induced periodontitis.Materials and methodsTwenty Wistar rats were used, and a cotton ligature was place in a subgingival position encircling the entire cervix of the first molar of the left (ipsilateral) side of the mandible. The right (contralateral) side of the mandible had no ligature placed and was used as control. After the ligature placement, animals were randomly assigned to two experimental groups (n=10): 1) rats with ligature + vehicle (saline; 10 mL/kg; orally) and 2) rats with ligature + simvastatin (25 mg/kg; orally). After 14 days of treatment, the animals were euthanized by anesthetic overdose and the gingival tissue was removed and homogenized in appropriate buffer. MMP-2 and -9 release as well as the IL-10 and TNF-α levels were detected by enzyme-linked immunosorbent assay. Statistical comparison was performed by unpaired Student’s t-test, with p<0.05 representing significance.ResultsNo differences were observed for TNF-α production between the groups (p>0.05). However, IL-10 was upregulated in simvastatin-treated animals (1.8-fold increase) in comparison with the vehicle-treated group (p<0.05). Simvastatin reduced the gingival levels of MMP-9 (64.3%) in comparison with vehicle-treated samples (p<0.05).ConclusionOral treatment with simvastatin increased the release of IL-10 and reduced the MMP-9 in ligature-induced periodontitis model in rats.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis

Júnior¹,

Macedo²,

Abdalla³

et al. 2017

CCIDE

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“…We isolated the synovial cells from synovial tissue of patients who underwent joint replacement surgery due to severe OA. Previous studies have indicated these pathological tissues express both TLR7 and TLR8 with elevated production of various cytokines, contributing to extensive articular destruction and functional decline 41 , 42 . CU-CPT8m showed significant inhibitory effects in suppressing the spontaneous release of TNF-α and IL-1β from synovial membrane cultures ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Small-molecule inhibition of TLR8 through stabilization of its resting state

et al. 2017

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Endosomal Toll-like receptors (TLR3/7/8/9) are highly analogous sensors for various viral or bacterial RNA/DNA molecular patterns. Nonetheless, few small-molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.

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“…It has long been established that statins including simvastatin can reduce cytokine production in monocytes from patients with hypercholesterolemia under toll-like receptor (TLR) stimulation conditions. [36][37][38] More recently, statin therapy has been shown to reduce levels of serum IL-1b and to reduce the levels of NLRP3 gene expression in PBMCs from patients with cardiovascular disease. 23 However, these studies do not include an analysis of known prominent mediators of sterile atherogenic inflammation such as CC used in this study, which we now know to be involved in NLRP3 inflammasome activation and subsequent IL-1b processing and activation.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Suppresses Interleukin Iβ Release in Human Peripheral Blood Mononuclear Cells Stimulated With Cholesterol Crystals

Boland

Gangadharan

Kavanagh

et al. 2018

J Cardiovasc Pharmacol Ther

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Statins are mainstream therapy in the treatment and prevention of cardiovascular disease through inhibitory effects on cholesterol synthesis. However, statins' beneficial effects in cardiovascular disease may also be attributable to their role as anti-inflammatory mediators. Here, we investigated the effects of simvastatin treatment on expression levels of interleukin (IL) 1β in both patient with hyperlipidemia and healthy human peripheral blood mononuclear cells (PBMCs) using cholesterol crystals (CC), a cardiovascular pathogenic stimulus for activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. Cholesterol crystal-induced NLRP3 inflammasome activation was used to trigger maturation and release of IL-1β in PBMCs. Specifically, isolated PBMCs from patients with hyperlipidemia at baseline and following 8 weeks of in vivo treatment with simvastatin (10-20 mg) daily were stimulated with lipopolysaccharide (LPS; 100 ng/mL) for 3 hours to induce proIL-Iβ expression followed by CC (2 mg/mL) stimulation for further 18 hours to activate the NLRP3 inflammasome complex to induce maturation/activation of IL-1β. Peripheral blood mononuclear cells were also isolated from healthy donors and stimulated in vitro with simvastatin (50, 25, 5, and 2 µmol/L) prior to stimulation with LPS and CC as described above. The effects of simvastatin treatment on levels of IL-1β expression were determined by enzyme-linked immunosorbent assay and western blot. Both in vitro and in vivo treatments with simvastatin led to a significant reduction in the levels of expression of IL-1β in response to stimulation with CC. Simvastatin inhibits the expression and activation of IL-1β induced by CC in PBMCs, which may contribute to its protective role in patients with cardiovascular disease.

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Simvastatin Inhibits Toll-like Receptor 8 (TLR8) Signaling in Primary Human Monocytes and Spontaneous Tumor Necrosis Factor Production from Rheumatoid Synovial Membrane Cultures

Cited by 11 publications

References 47 publications

Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis

Simvastatin modulates gingival cytokine and MMP production in a rat model of ligature-induced periodontitis

Small-molecule inhibition of TLR8 through stabilization of its resting state

Simvastatin Suppresses Interleukin Iβ Release in Human Peripheral Blood Mononuclear Cells Stimulated With Cholesterol Crystals

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