4-O-Methylgallic acid suppresses inflammation-associated gene expression by inhibition of redox-based NF-kappaB activation.
4-O-methylgallic acid (4-OMGA) is an in vivo major metabolite of gallic acid which is abundant in red wine, tea, legumes and fruit. We examined the in vitro and in vivo effects of 4-OMGA on the production and expression of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). 4-OMGA inhibited the expression and production of these inflammatory genes and mediators in RAW264.7 cells and primary macrophages stimulated with lipopolysaccharide (LPS). This compound also reduced the serum levels of these inflammatory mediators in endotoxemic mice. 4-OMGA inhibited iNOS promoter activity and NF-kappaB activation in LPS-treated RAW264.7 cells. 4-OMGA inhibited the LPS-mediated increase in reactive oxygen species production and exogenous H(2)O(2)-induced NF-kappaB activation. Moreover, this compound blocked IkappaBalpha phosphorylation and degradation and nuclear translocation of the cytosolic NF-kappaB p65 subunit, which highly correlated with its inhibitory effect on IkappaB kinase activity and inflammatory mediator production. These results suggest that 4-OMGA suppresses inflammation-associated gene expression by blocking NF-kappaB activation through the inhibition of redox-sensitive IkappaB kinase activity, suggesting that this compound may be beneficial for treating endotoxemia.
Na
Hee-Jun
HJ
Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea.
Lee
Gwangsoo
G
Oh
Heung-Young
HY
Jeon
Ki-Suk
KS
Kwon
Ho-Jeong
HJ
Ha
Kwon-Soo
KS
Lee
Hansoo
H
Kwon
Young-Guen
YG
Kim
Young-Myeong
YM
D000818:Animals; D002460:Cell Line; D019446:Endotoxemia / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
D018836:Inflammation Mediators; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C024272:3,5-dihydroxy-4-methoxybenzoic acid; D005707:Gallic Acid