Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Biochem Biophys Res Commun. 2014 Feb 21;444(4):555-61. doi: 10.1016/j.bbrc.2014.01.101. Epub 2014 Jan 29.
Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored. Herein we report a unique and Nrf2-dependent anti-inflammatory profile of dh404 in inflamed macrophages. In lipopolysaccharide (LPS)-inflamed RAW264.7 macrophages, dh404 dramatically suppressed the expression of pro-inflammatory cytokines including inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β), while minimally regulating the expression of interleulin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNFα). Dh404 potently activated Nrf2 signaling; however, it did not affect LPS-induced NF-κB activity. Dh404 did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages. Moreover, knockout of Nrf2 blocked the dh404-induced anti-inflammatory responses in LPS-inflamed macrophages. These results demonstrated that dh404 suppresses pro-inflammatory responses in macrophages via an activation of Nrf2 independently of Keap1 and NF-κB, suggesting a unique therapeutic potential of dh404 for specific targeting a Nrf2-mediated resolution of inflammation.
核因子红细胞 2 相关因子 (Nrf2) 是各种器官系统中细胞防御各种病理应激的主要调节剂，因此 Nrf2 已成为治疗和/或预防人类疾病的有吸引力的药物靶点。几种合成的齐墩果酸三萜类化合物，包括二氢-CDDO-三氟乙基酰胺 (dh404)，似乎是 Nrf2 的有效激活剂，并在多种疾病模型中表现出化学预防的前景。虽然 Nrf2 激活剂的药理学功效可能取决于特定靶器官中特定细胞类型的 Nrf2 激活的性质，但 Nrf2 在介导 Nrf2 激活化合物在各种细胞类型中的生物学效应的确切作用仍有待进一步探索。本文报道了 dh404 在炎症巨噬细胞中独特的、依赖于 Nrf2 的抗炎特征。在脂多糖 (LPS) 激活的 RAW264.7 巨噬细胞中，dh404 显著抑制了促炎细胞因子的表达，包括诱导型一氧化氮合酶 (iNOS)、单核细胞趋化蛋白-1 (MCP-1) 和巨噬细胞炎症蛋白-1β (MIP-1β)，同时最小程度地调节白细胞介素-6 (IL-6)、IL-1β 和肿瘤坏死因子α (TNFα) 的表达。Dh404 强烈激活了 Nrf2 信号通路；然而，它并没有影响 LPS 诱导的 NF-κB 活性。Dh404 并没有打断 Nrf2 与内源性抑制剂 Kelch-like ECH associating protein 1 (Keap1) 在巨噬细胞中的相互作用。此外，Nrf2 的敲除阻断了 dh404 在 LPS 激活的巨噬细胞中诱导的抗炎反应。这些结果表明，dh404 通过激活 Nrf2 抑制巨噬细胞中的促炎反应，这种作用独立于 Keap1 和 NF-κB，这表明 dh404 具有独特的治疗潜力，可用于针对 Nrf2 介导的炎症消退的特定靶向治疗。
