Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Chongqing Academy of Animal Sciences, Chongqing 402460, PR China.
Institute of Animal Nutrition, Sichuan Agricultural University, Sichuan Province, Chengdu 611130, PR China; Key Laboratory of Animal Disease-resistant Nutrition, Sichuan Province, Chengdu 611130, PR China.
Int J Biol Macromol. 2021 Dec 1;192:241-249. doi: 10.1016/j.ijbiomac.2021.09.163. Epub 2021 Oct 4.
Intestinal epithelial cells (IECs) offer a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestine. However, the influence of IECs on the development and regulation of mucosal immunity to infection is unknown. Here, we show that the porcine β-defensin 114 (PBD114) is an endotoxin-responsive gene expressed in IECs. Analysis on expression profiling of PBD114 gene using an infected porcine model and IPEC-J2 cells unveiled a pattern of induction in response to stimulation of various toll-like receptors (TLRs). By means of promoter analysis, PBD114 was found to be a NF-κB-dependent gene. Importantly, PBD114 suppresses endotoxin-induced inflammation and apoptosis in IECs through downregulation of two critical inflammation-associated signaling proteins, NF-kappa-B inhibitor alpha (IkB-α) and extracellular signal-regulated kinase1/2 (ERK1/2). PBD114 also suppresses inflammation and IEC apoptosis in mice exposed to bacterial endotoxins. Thus, we propose that TLR-activated NF-kB rapidly increases the expression of PBD114 that operates a feedback control of the NF-kB-dependent inflammation. The NF-kB-dependent induction of PBD114 may be a key event through which the mammalian host maintains intestinal epithelium homeostasis in response to various infections or diseases.
肠道上皮细胞 (IECs) 为胃肠道中的共生微生物和病原微生物提供了主要的物理屏障。然而，IECs 对感染性黏膜免疫的发展和调节的影响尚不清楚。在这里，我们表明猪 β-防御素 114 (PBD114) 是一种在 IECs 中表达的内毒素反应性基因。使用感染猪模型和 IPEC-J2 细胞对 PBD114 基因的表达谱进行分析，揭示了对各种 Toll 样受体 (TLR) 刺激的诱导模式。通过启动子分析，发现 PBD114 是一种 NF-κB 依赖性基因。重要的是，PBD114 通过下调两种关键的炎症相关信号蛋白 NF-kappa-B 抑制剂 alpha (IkB-α) 和细胞外信号调节激酶 1/2 (ERK1/2)，抑制 IEC 中的内毒素诱导的炎症和细胞凋亡。PBD114 还抑制了暴露于细菌内毒素的小鼠中的炎症和 IEC 凋亡。因此，我们提出 TLR 激活的 NF-κB 可迅速增加 PBD114 的表达，从而对 NF-κB 依赖性炎症进行反馈控制。NF-κB 依赖性诱导的 PBD114 可能是哺乳动物宿主在应对各种感染或疾病时维持肠道上皮细胞内稳态的关键事件。
