Faculty of Life Sciences, University of Manchester, Manchester, UK.
Br J Pharmacol. 2009 Aug;157(8):1318-29. doi: 10.1111/j.1476-5381.2009.00331.x.
Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine-expressing or cytokine-responsive cells. Interleukin-1 (IL-1) family cytokines are key pro-inflammatory mediators, and blockade of the IL-1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL-1 extracellular actions. Here we review evidence that suggests IL-1 family members have dual functionality. Several IL-1 family members have been detected inside the nuclei of IL-1-expressing or IL-1-responsive cells, and intranuclear IL-1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL-1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL-1 family members represent a new and potentially important area of IL-1 biology and may have implications for the future development of anti-IL-1 therapies.
失调的炎症反应导致外周和中枢神经系统疾病的发生。细胞因子是炎症的协调者，最初被定义为分泌的介质，从表达细胞中释放出来，激活反应细胞的质膜受体。然而，现在已经认识到一组细胞因子具有双重功能。除了它们的细胞外作用外，这些细胞因子还在表达细胞因子或对细胞因子有反应的细胞的核内发挥作用。白细胞介素-1（IL-1）家族细胞因子是关键的促炎介质，阻断炎症性疾病中的 IL-1 系统是一个有吸引力的治疗目标。所有目前的治疗方法都针对 IL-1 的细胞外作用。在这里，我们回顾了表明 IL-1 家族成员具有双重功能的证据。已经在表达或对 IL-1 有反应的细胞的核内检测到几种 IL-1 家族成员，并且据报道核内 IL-1 调节基因转录和 mRNA 剪接。然而，还需要进一步的工作来确定 IL-1 核内作用对疾病发病机制的影响。IL-1 家族成员的核内作用代表了 IL-1 生物学的一个新的、潜在的重要领域，可能对未来抗 IL-1 治疗的发展产生影响。
