Kunsch Charles, Luchoomun Jayraz, Chen Xi-Lin, Dodd Geraldine L, Karu Kanika S, Meng Charles Q, Marino Elaine M, Olliff Lyn K, Piper J Daniel, Qiu Fei-Hua, Sikorski James A, Somers Patricia K, Suen Ki-Ling, Thomas Suzanne, Whalen Anne M, Wasserman Martin A, Sundell Cynthia L
Department of Discovery Research, AtheroGenics, Inc., Alpharetta, GA 30004, USA.
J Pharmacol Exp Ther. 2005 May;313(2):492-501. doi: 10.1124/jpet.104.080804. Epub 2005 Feb 8.
The pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, is regulated, at least in part, by modulation of oxidation-reduction (redox) homeostasis and the expression of redox-sensitive inflammatory genes including adhesion molecules, chemokines, and cytokines. AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid] is a novel, orally active, phenolic antioxidant and anti-inflammatory compound with antirheumatic properties. To elucidate its anti-inflammatory mechanisms, we evaluated AGIX-4207 for a variety of cellular, biochemical, and molecular properties. AGIX-4207 exhibited potent antioxidant activity toward lipid peroxides in vitro and displayed enhanced cellular uptake relative to a structurally related drug, probucol. This resulted in potent inhibition of cellular levels of reactive oxygen species in multiple cell types. AGIX-4207 selectively inhibited tumor necrosis factor (TNF)-alpha-inducible levels of the redox-sensitive genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, with less inhibition of E-selectin, and no effect on intracellular adhesion molecule-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as lipopolysaccharide-induced release of TNF-alpha, IL-1beta, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-alpha-induced nuclear translocation of nuclear factor of the kappa-enhancer in B cells (NF-kappaB), suggesting that the mechanism of action is independent of this redox-sensitive transcription factor. Taken together, these results provide a mechanistic framework for understanding the anti-inflammatory and antirheumatic activity of AGIX-4207 and provide further support for the view that inhibition of redox-sensitive inflammatory gene expression is an attractive approach for the treatment of chronic inflammatory diseases.
包括类风湿关节炎在内的慢性炎症性疾病的发病机制至少部分受到氧化还原（redox）稳态调节以及对氧化还原敏感的炎症基因（包括黏附分子、趋化因子和细胞因子）表达的调控。AGIX - 4207 [2 - [4 - [[1 - [[3,5 - 双（1,1 - 二甲基乙基）- 4 - 羟基苯基]硫基]- 1 - 甲基乙基]硫基]- 2,6 - 双（1,1 - 二甲基乙基）苯氧基]乙酸]是一种新型的、口服活性的、具有抗风湿特性的酚类抗氧化剂和抗炎化合物。为阐明其抗炎机制，我们对AGIX - 4207的多种细胞、生化和分子特性进行了评估。AGIX - 4207在体外对脂质过氧化物表现出强大的抗氧化活性，并且相对于结构相关药物普罗布考显示出增强的细胞摄取。这导致在多种细胞类型中有效抑制活性氧的细胞水平。AGIX - 4207选择性抑制肿瘤坏死因子（TNF）-α诱导的对氧化还原敏感的基因（血管细胞黏附分子- 1和单核细胞趋化蛋白- 1）的表达水平，对E - 选择素的抑制作用较小，对内皮细胞中细胞间黏附分子- 1的表达无影响。此外，AGIX - 4207抑制细胞因子诱导的内皮细胞和人成纤维样滑膜细胞中单核细胞趋化蛋白- 1、白细胞介素（IL）- 6和IL - 8的水平，以及脂多糖诱导的人外周血单核细胞中TNF -α、IL - 1β和IL - 6的释放。AGIX - 4207不抑制TNF -α诱导的B细胞中κ - 增强子核因子（NF -κB）的核转位，表明其作用机制独立于这种对氧化还原敏感的转录因子。综上所述，这些结果为理解AGIX - 4207的抗炎和抗风湿活性提供了一个机制框架，并进一步支持了抑制对氧化还原敏感的炎症基因表达是治疗慢性炎症性疾病的一种有吸引力的方法这一观点。
