Schisandra chinensis α-iso-cubebenol induces heme oxygenase-1 expression through PI3K/Akt and Nrf2 signaling and has anti-inflammatory activity in Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages

Heme oxygenase-1 (HO-1) is a potent anti-inflammatory molecule that regulates pro-inflammatory mediators. Several studies have indicated that HO-1 expression is induced by a variety of stimuli such as lipopolysaccharide (LPS), cytokines, oxidative stress, and antioxidant phytochemicals. In this study, we assessed the anti-inflammatory effects of a novel alpha-iso-cubebenol isolated from dried fruits of Schisandra chinensis in human macrophage THP-1 cells and investigated the involvement of HO-1 signaling. We first observed that alpha-iso-cubebenol induced HO-1 mRNA and protein expression in a dose- and time-dependent manner via activation of erythroid-specific nuclear factor-regulated factor 2 (Nrf2). We also found that alpha-iso-cubebenol induced phosphorylation of phosphoinositide 3-kinase (PI3K)/Akt and extracellular-regulated kinase (ERK) in a time-dependent manner. Furthermore, treatment of THP-1 cells with inhibitors and siRNA specific for PI3K/Akt and ERK decreased the expression of HO-1. These results suggested that alpha-iso-cubebenol induced HO-1 expression through the activation of PI3K/Akt, ERK, and Nrf2 signaling. Next, alpha-iso-cubebenol strongly inhibited Porphyromonas gingivalis LPS-stimulated pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, and IL-12). Moreover, we observed that alpha-iso-cubebenol treatment inhibited nuclear levels and activity of NF-kappa B in a dose-dependent manner. Additionally, treatment with tin-protoporphyrin (snPP), a selective inhibitor of HO-1, reversed the alpha-iso-cubebenol-mediated inhibition of P. gingivalis LPS-induced pro-inflammatory cytokines. Hence, alpha-iso-cubebenol might induce anti-inflammatory effects on P. gingivalis LPS-stimulated human THP-1 macrophages by mediating the activation of PI3k/Akt and ERK that leads to over-expression of HO-1 and Nrf-2. These findings suggest that alpha-iso-cubebenol may be considered as a novel therapeutic agent to ameliorate periodontitis. (C) 2011 Elsevier B.V. All rights reserved.