Sodium butyrate up-regulates cathelicidin gene expression via activator protein-1 and histone acetylation at the promoter region in a human lung epithelial cell line, EBC-1.
The antimicrobial protein cathelicidin is considered to play an important role in the defense mechanisms against bacterial infection. Recent studies show that sodium butyrate induces cathelicidin gene expression in human colonic, gastric and hepatic cells. However, little is known about the precise regulatory mechanisms underlying sodium butyrate-induced cathelicidin gene expression. In this study, we examined the regulatory mechanisms involved in sodium butyrate-induced cathelicidin gene expression using a human lung epithelial cell line, EBC-1. Our results indicate that sodium butyrate induces both cathelicidin mRNA and protein expression. Moreover, deletion or mutation of a putative activator protein-1 (AP-1) binding site in the cathelicidin gene promoter abrogated the response to sodium butyrate stimulation. Three different mitogen-activated protein (MAP) kinase inhibitors suppressed sodium butyrate-induced transactivation of the cathelicidin promoter. Electrophoretic mobility shift assays (EMSA) showed that nuclear extracts prepared from sodium butyrate-stimulated EBC-1 cells generated specific binding to probe including a putative AP-1 binding site in the cathelicidin gene promoter. Furthermore, chromatin immunoprecipitation (ChIP) assays demonstrated that sodium butyrate augmented histone acetylation of the cathelicidin promoter in EBC-1 cells. Therefore, these results indicate that AP-1 and histone acetylation of the cathelicidin promoter play a critical role in the regulation of inducible cathelicidin gene expression in EBC-1 cells stimulated with sodium butyrate.
Kida
Yutaka
Y
Department of Bacteriology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
Shimizu
Takashi
T
Kuwano
Koichi
K
D000107:Acetylation; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002087:Butyrates / Q000494:pharmacology*; D054804:Cathelicidins; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects*
D023181:Antimicrobial Cationic Peptides; D002087:Butyrates; D054804:Cathelicidins; D006657:Histones; D011506:Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1