Giridharan Sivagami, Srinivasan Mythily
Department of Oral Medicine, Madha Dental College, Kundrathur, Chennai, TN, India.
Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indiana University Purdue University at Indianapolis, Indianapolis, IN, USA,
J Inflamm Res. 2018 Oct 30;11:407-419. doi: 10.2147/JIR.S140188. eCollection 2018.
The transcription factor NF-κB is a critical regulator of immune and inflammatory responses. In mammals, the NF-κB/Rel family comprises five members: p50, p52, p65 (Rel-A), c-Rel, and Rel-B proteins, which form homo- or heterodimers and remain as an inactive complex with the inhibitory molecules called IκB proteins in resting cells. Two distinct NF-κB signaling pathways have been described: 1) the canonical pathway primarily activated by pathogens and inflammatory mediators, and 2) the noncanonical pathway mostly activated by developmental cues. The most abundant form of NF-κB activated by pathologic stimuli via the canonical pathway is the p65:p50 heterodimer. Disproportionate increase in activated p65 and subsequent transactivation of effector molecules is integral to the pathogenesis of many chronic diseases such as the rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and even neurodegenerative pathologies. Hence, the NF-κB p65 signaling pathway has been a pivotal point for intense drug discovery and development. This review begins with an overview of p65-mediated signaling followed by discussion of strategies that directly target NF-κB p65 in the context of chronic inflammation.
转录因子NF-κB是免疫和炎症反应的关键调节因子。在哺乳动物中，NF-κB/Rel家族由五个成员组成：p50、p52、p65（Rel-A）、c-Rel和Rel-B蛋白，它们形成同二聚体或异二聚体，并在静息细胞中与称为IκB蛋白的抑制分子形成无活性复合物。已描述了两种不同 的NF-κB信号通路：1）主要由病原体和炎症介质激活的经典通路，以及2）主要由发育信号激活的非经典通路。通过经典通路由病理刺激激活的最丰富形式的NF-κB是p65:p50异二聚体。活化的p65的过度增加以及效应分子的随后反式激活是许多慢性疾病如类风湿性关节炎、炎症性肠病、多发性硬化症甚至神经退行性病变发病机制的组成部分。因此，NF-κB p65信号通路一直是药物研发的关键点。本综述首先概述p65介导的信号传导，然后讨论在慢性炎症背景下直接靶向NF-κB p65的策略。
