Dataset Information
Romidepsin suppresses monosodium urate crystal-induced cytokine production through upregulation of suppressor of cytokine signaling 1 expression.
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ABSTRACT: Background
Acute gouty arthritis currently is the most common form of inflammatory arthritis in developed countries. Treatment is still suboptimal. Dosage of urate-lowering therapy is often too low to reach target urate levels, and adherence to therapy is poor. In this study, we therefore explore a new treatment option to limit inflammation in acute gout: specific histone deacetylase (HDAC) inhibition.Methods
Peripheral blood mononuclear cells (PBMCs) were cultured with a combination of monosodium urate crystals (MSU) and palmitic acid (C16.0) in order to activate the NLRP3 inflammasome and induce IL-1? production. HDAC inhibitors and other compounds were added beforehand with a 1-h pre-incubation period.Results
The HDAC1/2 inhibitor romidepsin was most potent in lowering C16.0+MSU-induced IL-1? production compared to other specific class I HDAC inhibitors. At 10?nM, romidepsin decreased IL-1?, IL-1Ra, IL-6, and IL-8 production. IL-1? mRNA was significantly decreased at 25?nM. Although romidepsin increased PTEN expression, PBMCs from patients with germline mutations in PTEN still responded well to romidepsin. Romidepsin also increased SOCS1 expression and blocked STAT1 and STAT3 activation. Furthermore, experiments with bortezomib showed that blocking the proteasome reverses the cytokine suppression by romidepsin.Conclusions
Our results show that romidepsin is a very potent inhibitor of C16.0+MSU-induced cytokines in vitro. Romidepsin upregulated transcription of SOCS1, which was shown to directly target inflammatory signaling molecules for proteasomal degradation. Inhibiting the proteasome therefore reversed the cytokine-suppressive effects of romidepsin. HDAC1/2 dual inhibition could therefore be a highly potent new treatment option for acute gout, although safety has to be determined in vivo.
SUBMITTER: Cleophas MCP
PROVIDER: S-EPMC6366029 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
Romidepsin suppresses monosodium urate crystal-induced cytokine production through upregulation of suppressor of cytokine signaling 1 expression.
Arthritis research & therapy 20190206 1
<h4>Background</h4>Acute gouty arthritis currently is the most common form of inflammatory arthritis in developed countries. Treatment is still suboptimal. Dosage of urate-lowering therapy is often too low to reach target urate levels, and adherence to therapy is poor. In this study, we therefore explore a new treatment option to limit inflammation in acute gout: specific histone deacetylase (HDAC) inhibition.<h4>Methods</h4>Peripheral blood mononuclear cells (PBMCs) were cultured with a combina ...[more]
