State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
Hubei Provincial Institute of Veterinary Drug Control, Wuhan 430068, P.R. China.
Sci Rep. 2016 Jun 14;6:27876. doi: 10.1038/srep27876.
Cecropins are peptide antibiotics used as drugs and feed additives. Cecropin B can inhibit the expression of CYP3A29, but the underlying mechanisms remain unclear. The present study was designed to determine the mechanisms responsible for the effects of cecropin B on CYP3A29 expression, focusing on the Toll-like receptors (TLRs) and NF-κB pathways. Our results indicated that the CYP3A29 expression was inhibited by cecropin B, which was regulated by pregnane X receptor (PXR) in a time- and dose-dependent manner. Cecropin B-induced NF-κB activation played a pivotal role in the suppression of CYP3A29 through disrupting the association of the PXR/retinoid X receptor alpha (RXR-α) complex with DNA sequences. NF-κB p65 directly interacted with the DNA-binding domain of PXR, suppressed its expression, and inhibited its transactivation, leading to the downregulation of the PXR-regulated CYP3A29 expression. Furthermore, cecropin B activated pig liver cells by interacting with TLRs 2 and 4, which modulated NF-κB-mediated signaling pathways. In conclusion, cecropin B inhibited the expression of CYP3A29 in a TLR/NF-κB/PXR-dependent manner, which should be considered in future development of cecropins and other antimicrobial peptides.
抗菌肽蜂毒素可用作药物和饲料添加剂。蜂毒素 B 可以抑制 CYP3A29 的表达，但具体机制尚不清楚。本研究旨在确定蜂毒素 B 对 CYP3A29 表达的影响机制，重点关注 Toll 样受体 (TLRs) 和 NF-κB 途径。结果表明，蜂毒素 B 以时间和剂量依赖的方式通过妊娠相关蛋白 X 受体 (PXR) 调节 CYP3A29 的表达。蜂毒素 B 诱导的 NF-κB 激活通过破坏 PXR/视黄酸 X 受体 α (RXR-α) 复合物与 DNA 序列的结合，在抑制 CYP3A29 表达中起关键作用。NF-κB p65 直接与 PXR 的 DNA 结合域相互作用，抑制其表达并抑制其反式激活，导致 PXR 调节的 CYP3A29 表达下调。此外，蜂毒素 B 通过与 TLR2 和 TLR4 相互作用激活猪肝细胞，调节 NF-κB 介导的信号通路。总之，蜂毒素 B 以 TLR/NF-κB/PXR 依赖的方式抑制 CYP3A29 的表达，这在蜂毒素和其他抗菌肽的未来开发中应予以考虑。
