Hannigan G E, Williams B R
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Science. 1991 Jan 11;251(4990):204-7. doi: 10.1126/science.1898993.
Molecular mechanisms that mediate signal transduction by growth inhibitory cytokines are poorly understood. Type I (alpha and beta) interferons (IFNs) are potent growth inhibitory cytokines whose biological activities depend on induced changes in gene expression. IFN-alpha induced the transient activation of phospholipase A2 in 3T3 fibroblasts and rapid hydrolysis of [3H]arachidonic acid (AA) from prelabeled phospholipid pools. The phospholipase inhibitor, bromophenacyl bromide (BPB), specifically blocked IFN-induced binding of nuclear factors to a conserved, IFN-regulated enhancer element, the interferon-stimulated response element (ISRE). BPB also caused a dose-dependent inhibition of IFN-alpha-induced ISRE-dependent transcription in transient transfection assays. Specific inhibition of AA oxygenation by eicosatetraynoic acid prevented IFN-alpha induction of factor binding to the ISRE. Treatment of intact cells with inhibitors of fatty acid cyclooxygenase or lipoxygenase enzymes resulted in amplification of IFN-alpha-induced ISRE binding and gene expression. Thus, IFN-alpha receptor-coupled AA hydrolysis may function in activation of latent transcription factors by IFN-alpha and provides a system for studying the role of AA metabolism in transduction of growth inhibitory signals.
介导生长抑制性细胞因子信号转导的分子机制仍知之甚少。I型（α和β）干扰素（IFN）是强效的生长抑制性细胞因子，其生物学活性取决于基因表达的诱导变化。IFN-α可诱导3T3成纤维细胞中磷脂酶A2的瞬时激活，并促使预标记磷脂池中的[3H]花生四烯酸（AA）快速水解。磷脂酶抑制剂溴苯甲酰溴（BPB）特异性地阻断了IFN诱导的核因子与保守的、IFN调节的增强子元件——干扰素刺激反应元件（ISRE）的结合。在瞬时转染实验中，BPB还对IFN-α诱导的ISRE依赖性转录产生了剂量依赖性抑制作用。二十碳四烯酸对AA氧化的特异性抑制可阻止IFN-α诱导因子与ISRE的结合。用脂肪酸环氧化酶或脂氧合酶抑制剂处理完整细胞，会导致IFN-α诱导的ISRE结合和基因表达增强。因此，IFN-α受体偶联的AA水解可能在IFN-α激活潜在转录因子的过程中发挥作用，并为研究AA代谢在生长抑制信号转导中的作用提供了一个系统。
