Cuesta Natalia, Staniszewska Anna D, Moreno Cristóbal, Punzón Carmen, Fresno Manuel
Department of Cell Biology and Histology, School of Medicine, Universidad Complutense de Madrid, Avda Complutense s/n, 28040 Madrid, Spain.
Department of Biochemistry and Molecular Biology, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Nicolás Cabrera 1, 28049 Madrid, Spain.
Biology (Basel). 2025 Jan 3;14(1):33. doi: 10.3390/biology14010033.
This study investigates the role of NIK in activating specific inflammatory genes in macrophages, focusing on the effect of a mutation in NIK found in alymphoplasia (/) mice. Mouse peritoneal macrophages from / mice showed a severe defect in the production of some pro-inflammatory cytokines, such as IL-12. This effect seemed to take place at the transcriptional level, as shown by the reduced transcription of and in / macrophages after exposure to the TLR4 agonist LPS. Immunoprecipitation studies showed that the binding of NIK to c-Rel was not efficient in RAW 264.7 cells over-expressing the / mutation. In addition, the shuttling of c-Rel to the nucleus was shown to be impaired in / macrophages in response to LPS. When looking more specifically at the regulation of the promoter, we found that c-Rel bound to the NF-kB consensus sequence in macrophages from WT mice 1 hr. after LPS challenge, whereas in / macrophages, the transcription factor bound to the promoter was p65. These findings indicate that NIK is essential for efficient c-Rel activation and proper inflammatory responses. NIK dysfunction could lead to weakened immune responses, and targeting this pathway may help in developing therapies for immune-related conditions.
本研究调查了NIK在激活巨噬细胞中特定炎症基因方面的作用，重点关注在无淋巴细胞症（aly）小鼠中发现的NIK突变的影响。来自aly小鼠的小鼠腹腔巨噬细胞在某些促炎细胞因子（如IL-12）的产生方面表现出严重缺陷。如暴露于TLR4激动剂LPS后aly巨噬细胞中 和 的转录减少所示，这种效应似乎发生在转录水平。免疫沉淀研究表明，在过表达aly突变的RAW 264.7细胞中，NIK与c-Rel的结合效率不高。此外，响应LPS时，aly巨噬细胞中c-Rel向细胞核的穿梭被证明受损。当更具体地研究 启动子的调控时，我们发现LPS刺激1小时后，WT小鼠巨噬细胞中的c-Rel与NF-κB共有序列结合，而在aly巨噬细胞中，与启动子结合的转录因子是p65。这些发现表明，NIK对于有效的c-Rel激活和适当的炎症反应至关重要。NIK功能障碍可能导致免疫反应减弱，针对该途径可能有助于开发针对免疫相关病症的治疗方法。
