Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-κB factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model of experimental colitis, we established that Nfkb2-mediated regulations escalated the RelA-driven proinflammatory gene response in intestinal epithelial cells, exacerbating the infiltration of inflammatory cells and colon pathologies. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-κB dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.

RelA/NF-κB 因子的过度活性会加剧异常炎症，例如与炎症性肠病 (IBD) 相关的炎症。因此，典型的 NF-κB 模块介导来自潜在细胞质复合物的 RelA 二聚体的受控核激活。是什么引发了结肠炎肠道中的病理性 RelA 活性仍不清楚。非经典 NF-κB 通路通常促进涉及Nfkb2基因产物的免疫器官发生。由于 NF-κB 通路相互交织，我们想知道非规范信号传导是否会加重炎症 RelA 活性。我们的调查揭示了人类 IBD 中非典型途径的频繁参与。在实验性结肠炎的小鼠模型中，我们确定Nfkb2介导的调节增强了肠上皮细胞中 RelA 驱动的促炎基因反应，加剧了炎症细胞的浸润和结肠病理。我们的机制研究阐明，细胞自主Nfkb2信号传导补充了潜在的 NF-κB 二聚体，导致发炎结肠中过度活跃的典型 RelA 反应。总之，潜在 NF-κB 二聚体的调节似乎将非典型Nfkb2信号传导与 RelA 驱动的炎症病理联系起来，并可能提供治疗靶点。