title: C/EBPα and the Vitamin D Receptor Cooperate in the Regulation of Cathelicidin in Lung Epithelial Cells.
abstract: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) and the vitamin D receptor (VDR) have been reported to have an important role in the regulation of innate immunity. We earlier reported that the antimicrobial peptide cathelicidin is induced by 1,25(OH)2D3 in normal human bronchial epithelial cells with a resultant increase in antimicrobial activity against airway pathogens. In this study, we demonstrate that C/EBP alpha (C/EBPα) is a potent enhancer of human cathelicidin antimicrobial peptide (CAMP) gene transcription in human lung epithelial cells. In addition we found that C/EBPα functionally cooperates with VDR in the regulation of CAMP transcription. A C/EBP binding site was identified at -627/-619 within the CAMP promoter, adjacent to the vitamin D response element (VDRE; -615/-600). Mutation of this site markedly attenuated the transcriptional response to C/EBPα as well as to 1,25(OH)2D3, further indicating cooperation between these two factors in the regulation of CAMP. ChIP analysis using 1,25(OH)2D3 treated human lung epithelial cells showed C/EBPα and VDR binding to the CAMP promoter. C/EBPα has previously been reported to cooperate with Brahma (Brm), an ATPase that is component of the SWI/SNF chromatin remodeling complex. We found that dominant negative Brm significantly inhibited C/EBPα as well as 1,25(OH)2D3 mediated induction of CAMP transcription, suggesting the functional involvement of Brm. These findings define novel mechanisms involving C/EBPα, SWI/SNF, and 1,25(OH)2D3 in the regulation of CAMP in lung epithelial cells. These mechanisms of enhanced activation of the CAMP gene in lung epithelial cells suggest potential candidates for the development of modulators of innate immune responses for adjunct therapy in the treatment of airway infections.
authors: Department of Biochemistry and Molecular Biology, Rutgers, the State University of New Jersey, New Jersey Medical School, Newark, New Jersey.
authors: Puneet
authors: P
authors: Dhawan
authors: Department of Biochemistry and Molecular Biology, Rutgers, the State University of New Jersey, New Jersey Medical School, Newark, New Jersey.
authors: Ran
authors: R
authors: Wei
authors: Department of Biochemistry and Molecular Biology, Rutgers, the State University of New Jersey, New Jersey Medical School, Newark, New Jersey.
authors: Cheng
authors: C
authors: Sun
authors: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University Corvallis, Oregon.
authors: Adrian F
authors: AF
authors: Gombart
authors: Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California.
authors: H Phillip
authors: HP
authors: Koeffler
authors: Department of Oral Biology, University of Florida, College of Dentistry, Gainsville, Florida.
authors: Gill
authors: G
authors: Diamond
authors: Department of Biochemistry and Molecular Biology, Rutgers, the State University of New Jersey, New Jersey Medical School, Newark, New Jersey.
authors: Sylvia
authors: S
authors: Christakos
mesh_terms: D023181:Antimicrobial Cationic Peptides; D001665:Binding Sites / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002117:Calcitriol / Q000378:metabolism; D054804:Cathelicidins / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000276:immunology; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology
chemical_list: D023181:Antimicrobial Cationic Peptides; D022763:CCAAT-Enhancer-Binding Protein-alpha; D054804:Cathelicidins; D018167:Receptors, Calcitriol; D002117:Calcitriol