A novel mechanism for inhibition of lipopolysaccharide-induced proinflammatory cytokine production by valproic acid

The inhibitory effect of valproic acid (VPA) on lipopolysaccharide (LPS)-induced inflammatory response was studied by using mouse RAW 264.7 macrophage-like cells. WA pretreatment attenuated LPS-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt, but not nuclear factor (NF)-kappa B and mitogen-activated protein kinases. VPA reduced phosphorylation of MDM2, an ubiquitin ligase and then prevented LPS-induced p53 degradation, followed by enhanced p53 expression. Moreover, p53 small interfering RNA (siRNA) abolished the inhibitory action of VPA on LPS-induced NF-kappa B p65 transcriptional activation and further LPS-induced tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. WA prevented LPS-induced degradation of phosphatase and tensin homologue deleted on chromosome ten (PIEN) and up-regulated the PTEN expression. Taken together, VPA was suggested to down-regulate LPS-induced NF-kappa B-dependent transcriptional activity via impaired PI3K/Akt/MDM2 activation and enhanced p53 expression. A detailed mechanism for inhibition of LPS-induced inflammatory response by WA is discussed. (C) 2014 Elsevier B.V. All rights reserved.