非经典NF-κB信号通路在炎症性肠病病理生物学调节中的新作用
Emerging Roles for Noncanonical NF-κB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology.
作者信息
McDaniel Dylan K, Eden Kristin, Ringel Veronica M, Allen Irving C
机构信息
*Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia; and †Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, Virginia.
出版信息
Inflamm Bowel Dis. 2016 Sep;22(9):2265-79. doi: 10.1097/MIB.0000000000000858.
Crohn's disease and ulcerative colitis are common and debilitating manifestations of inflammatory bowel disease (IBD). IBD is characterized by a radical imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways in the gut. These pathways are controlled by NF-κB, which is a master regulator of gene transcription. In IBD patients, NF-κB signaling is often dysregulated resulting in overzealous inflammation. NF-κB activation occurs through 2 distinct pathways, defined as either canonical or noncanonical. Canonical NF-κB pathway activation is well studied in IBD and is associated with the rapid, acute production of diverse proinflammatory mediators, such as COX-2, IL-1β, and IL-6. In contrast to the canonical pathway, the noncanonical or "alternative" NF-κB signaling cascade is tightly regulated and is responsible for the production of highly specific chemokines that tend to be associated with less acute, chronic inflammation. There is a relative paucity of literature regarding all aspects of noncanonical NF-ĸB signaling. However, it is clear that this alternative signaling pathway plays a considerable role in maintaining immune system homeostasis and likely contributes significantly to the chronic inflammation underlying IBD. Noncanonical NF-κB signaling may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD. However, significant mechanistic insight is still required to translate the current basic science findings into effective therapeutic strategies.
克罗恩病和溃疡性结肠炎是炎症性肠病(IBD)常见且使人衰弱的表现形式。IBD的特征是肠道中促炎和抗炎信号通路的激活存在严重失衡。这些通路由NF-κB控制,NF-κB是基因转录的主要调节因子。在IBD患者中,NF-κB信号传导常常失调,导致过度炎症反应。NF-κB的激活通过2种不同的途径发生,即经典途径或非经典途径。经典NF-κB途径的激活在IBD中已得到充分研究,并且与多种促炎介质(如COX-2、IL-1β和IL-6)的快速、急性产生有关。与经典途径相反,非经典或“替代”NF-κB信号级联受到严格调控,负责产生高度特异性的趋化因子,这些趋化因子往往与不太急性的慢性炎症相关。关于非经典NF-κB信号传导的各个方面,相关文献相对较少。然而,很明显,这种替代信号通路在维持免疫系统稳态中发挥着相当重要的作用,并且可能对IBD潜在的慢性炎症有重大贡献。非经典NF-κB信号传导可能代表了寻找与IBD相关的治疗靶点和生物标志物的一个有前景的新方向。然而,仍需要深入的机制性见解,以便将当前的基础科学发现转化为有效的治疗策略。