Cecropin B Represses CYP3A29 Expression through Activation of the TLR2/4-NF-κB/PXR Signaling Pathway.
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.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
Xiaoqiao
X
Zhou
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
Xiaowen
X
Li
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
Xiliang
X
Wang
Hubei Provincial Institute of Veterinary Drug Control, Wuhan 430068, P.R. China.
Xiue
X
Jin
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
Deshi
D
Shi
Hubei Provincial Institute of Veterinary Drug Control, Wuhan 430068, P.R. China.
Jun
J
Wang
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, P.R. China.
Dingren
D
Bi
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019476:Insect Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D000074435:Peroxisome-Targeting Signal 1 Receptor / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000900:Anti-Bacterial Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D019476:Insect Proteins; D016328:NF-kappa B; D000074435:Peroxisome-Targeting Signal 1 Receptor; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C031162:cecropin B protein, Insecta; D051544:Cytochrome P-450 CYP3A