Bio-IT Fusion Technology Research Institute, Pusan National University, Busan, Republic of Korea.
Int Immunopharmacol. 2011 Nov;11(11):1907-15. doi: 10.1016/j.intimp.2011.07.023. Epub 2011 Aug 12.
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 α-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 α-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 α-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 α-iso-cubebenol induced HO-1 expression through the activation of PI3K/Akt, ERK, and Nrf2 signaling. Next, α-iso-cubebenol strongly inhibited Porphyromonas gingivalis LPS-stimulated pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-12). Moreover, we observed that α-iso-cubebenol treatment inhibited nuclear levels and activity of NF-κB in a dose-dependent manner. Additionally, treatment with tin-protoporphyrin (SnPP), a selective inhibitor of HO-1, reversed the α-iso-cubebenol-mediated inhibition of P. gingivalis LPS-induced pro-inflammatory cytokines. Hence, α-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 α-iso-cubebenol may be considered as a novel therapeutic agent to ameliorate periodontitis.
血红素加氧酶-1（HO-1）是一种有效的抗炎分子，可调节促炎介质。多项研究表明，HO-1 的表达受多种刺激诱导，如脂多糖（LPS）、细胞因子、氧化应激和抗氧化植物化学物质。在这项研究中，我们评估了从五味子干果中分离得到的新型α-异古巴醇在人巨噬细胞 THP-1 细胞中的抗炎作用，并研究了 HO-1 信号的参与。我们首先观察到，α-异古巴醇通过激活红细胞特异性核因子 2（Nrf2）以剂量和时间依赖的方式诱导 HO-1mRNA 和蛋白表达。我们还发现，α-异古巴醇以时间依赖的方式诱导磷酸肌醇 3-激酶（PI3K）/Akt 和细胞外调节激酶（ERK）的磷酸化。此外，用 PI3K/Akt 和 ERK 的抑制剂和 siRNA 处理 THP-1 细胞会降低 HO-1 的表达。这些结果表明，α-异古巴醇通过激活 PI3K/Akt、ERK 和 Nrf2 信号诱导 HO-1 的表达。接下来，α-异古巴醇强烈抑制牙龈卟啉单胞菌 LPS 刺激的促炎细胞因子（肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-6 和 IL-12）。此外，我们观察到，α-异古巴醇以剂量依赖的方式抑制 NF-κB 的核水平和活性。此外，用 HO-1 的选择性抑制剂锡原卟啉（SnPP）处理可逆转α-异古巴醇介导的对牙龈卟啉单胞菌 LPS 诱导的促炎细胞因子的抑制作用。因此，α-异古巴醇可能通过介导 PI3k/Akt 和 ERK 的激活来诱导对牙龈卟啉单胞菌 LPS 刺激的人 THP-1 巨噬细胞的抗炎作用，从而导致 HO-1 和 Nrf-2 的过度表达。这些发现表明，α-异古巴醇可能被认为是一种改善牙周炎的新型治疗剂。
