Dataset Information

WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages.

ABSTRACT:

Background and purpose

Hydroxamate derivatives have attracted considerable attention because of their broad pharmacological properties. Recent studies reported their potential use in the treatment of cardiovascular diseases, arthritis and infectious diseases. However, the mechanisms of the anti-inflammatory effects of hydroxamate derivatives remain to be elucidated. In an effort to develop a novel pharmacological agent that could suppress abnormally activated macrophages, we investigated a novel aliphatic hydroxamate derivative, WMJ-S-001, and explored its anti-inflammatory mechanisms.

Experimental approach

RAW264.7 macrophages were exposed to LPS in the absence or presence of WMJ-S-001. COX-2 expression and signalling molecules activated by LPS were assessed.

Key results

LPS-induced COX-2 expression was suppressed by WMJ-S-001. WMJ-S-001 inhibited p38MAPK, NF-?B subunit p65 and CCAAT/enhancer-binding protein (C/EBP)? phosphorylation in cells exposed to LPS. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) markedly inhibited LPS-induced p65 and C/EBP? phosphorylation and COX-2 expression. LPS-increased p65 and C/EBP? binding to the COX-2 promoter region was suppressed in the presence of WMJ-S-001. In addition, WMJ-S-001 suppression of p38MAPK, p65 and C/EBP? phosphorylation, and subsequent COX-2 expression were restored in cells transfected with a dominant-negative (DN) mutant of MAPK phosphatase-1 (MKP-1). WMJ-S-001 also caused an increase in MKP-1 activity in RAW264.7 macrophages.

Conclusions and implications

WMJ-S-001 may activate MKP-1, which then dephosphorylates p38MAPK, resulting in a decrease in p65 and C/EBP? binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated RAW264.7 macrophages. The present study suggests that WMJ-S-001 may be a potential drug candidate for alleviating LPS-associated inflammatory diseases.

SUBMITTER: Chen WC

PROVIDER: S-EPMC4376465 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages.

Chen Wei-Chuan WC Yen Chia-Sheng CS Huang Wei-Jan WJ Hsu Ya-Fen YF Ou George G Hsu Ming-Jen MJ

British journal of pharmacology 20150227 7

<h4>Background and purpose</h4>Hydroxamate derivatives have attracted considerable attention because of their broad pharmacological properties. Recent studies reported their potential use in the treatment of cardiovascular diseases, arthritis and infectious diseases. However, the mechanisms of the anti-inflammatory effects of hydroxamate derivatives remain to be elucidated. In an effort to develop a novel pharmacological agent that could suppress abnormally activated macrophages, we investigated ...[more]

PMID: 25521622

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Project description:Recent studies confirm that chronic low-grade inflammation is closely associated with metabolic syndromes, and anti-inflammatory therapy is a potential approach for treating cardiovascular diseases and type 2 diabetes. Accumulating evidence suggests that GPR120 activation is a feasible solution to ameliorating chronic inflammation and improving glucose metabolism. In this study we investigated whether ginsenoside Rb2 (Rb2), which exhibited regulatory activities in glucose and lipid metabolism, affected GPR120 expression in lipopolysaccharide (LPS)-activated mouse macrophage RAW264.7 cells, and examined the contribution of GPR120 activation to reducing the LPS-induced inflammatory response. LPS (100 ng/mL) activated the macrophages, resulting in dramatic increases in TNF-α, IL-6, IL-1β and NO production. Treatment with a ω-3 fatty acid α-linolenic acid (ALA, 50 μmol/L) produced moderate reduction in LPS-stimulated inflammatory cytokines and NO production (TNF-α and IL-6 were decreased by 46% and 42%, respectively). Pre-incubation with Rb2 (1 or 10 μmol/L) for 12 h before ALA treatment dramatically amplified the inhibitory effects of ALA (TNF-α and IL-6 were decreased by 74% and 86%, respectively). Compared to the treatment with ALA alone, pre-incubation with Rb2 resulted in a more prominent reduction in LPS-stimulated expression of iNOS and COX-2 and LPS-stimulated IKK/NF-κB phosphorylation and MAPK pathway activation. Rb2 (0.1-100 μmol/L) dose- and time-dependently increased both mRNA and protein expression of GPR120 in RAW264.7 cells, but treatment with Rb2 alone did not exert anti-inflammatory effect in LPS-activated RAW264.7 cells. In RAW264.7 cells transfected with GPR120 shRNA, the ameliorating effects of Rb2 on LPS-induced inflammation were abolished. In conclusion, Rb2 exerts anti-inflammatory effect in LPS-stimulated mouse macrophage RAW264.7 cells in vitro by increasing GPR120 expression and subsequently enhancing ω-3 fatty acid-induced GPR120 activation.

Dataset Information

WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages.

Similar Datasets

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