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WMJ ‐ S ‐001, a novel aliphatic hydroxamate derivative, exhibits anti‐inflammatory properties via MKP ‐1 in LPS ‐stimulated RAW 264.7 macrophages
Author(s) -
Chen WeiChuan,
Yen ChiaSheng,
Huang WeiJan,
Hsu YaFen,
Ou George,
Hsu MingJen
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13040
Subject(s) - phosphorylation , chemistry , mapk/erk pathway , phosphatase , transfection , microbiology and biotechnology , biochemistry , biology , gene
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 RAW 264.7 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 p38 MAPK , NF ‐κ B subunit p65 and CCAAT /enhancer‐binding protein ( C / EBP )β phosphorylation in cells exposed to LPS . Treatment of cells with a p38 MAPK inhibitor (p38 MAPK inhibitor III ) markedly inhibited LPS ‐induced p65 and C / EBP β phosphorylation and COX ‐2 expression. LPS ‐increased p65 and C / EBP β binding to the COX ‐2 promoter region was suppressed in the presence of WMJ ‐ S ‐001. In addition, WMJ ‐ S ‐001 suppression of p38 MAPK , p65 and C / EBP β 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 RAW 264.7 macrophages. Conclusions and Implications WMJ ‐ S ‐001 may activate MKP ‐1, which then dephosphorylates p38 MAPK , resulting in a decrease in p65 and C / EBP β binding to the COX ‐2 promoter region and COX ‐2 down‐regulation in LPS ‐stimulated RAW 264.7 macrophages. The present study suggests that WMJ ‐ S ‐001 may be a potential drug candidate for alleviating LPS ‐associated inflammatory diseases.