4-O-Methylgallic acid suppresses inflammation-associated gene expression by inhibition of redox-based NF-κB 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 E₂ (PGE₂) as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). 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-κB activation in LPS-treated RAW264.7 cells. 4-OMGA inhibited the LPS-mediated increase in reactive oxygen species production and exogenous H₂O₂-induced NF-κB activation. Moreover, this compound blocked IκBα phosphorylation and degradation and nuclear translocation of the cytosolic NF-κB p65 subunit, which highly correlated with its inhibitory effect on IκB kinase activity and inflammatory mediator production. These results suggest that 4-OMGA suppresses inflammation-associated gene expression by blocking NF-κB activation through the inhibition of redox-sensitive IκB kinase activity, suggesting that this compound may be beneficial for treating endotoxemia.