TitleC/EBPα and the Vitamin D Receptor Cooperate in the Regulation of Cathelicidin in Lung Epithelial Cells.
Publication TypeJournal Article
Year of Publication2015
AuthorsDhawan P, Wei R, Sun C, Gombart AF, H Koeffler P, Diamond G, Christakos S
JournalJ Cell Physiol
Volume230
Issue2
Pagination464-72
Date Published2015 Feb
ISSN1097-4652
KeywordsAntimicrobial Cationic Peptides, Binding Sites, Calcitriol, Cathelicidins, CCAAT-Enhancer-Binding Protein-alpha, Cell Line, Epithelial Cells, Humans, Lung, Promoter Regions, Genetic, Receptors, Calcitriol, Transcriptional Activation
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.

DOI10.1002/jcp.24729
Alternate JournalJ. Cell. Physiol.
PubMed ID25078430
Grant ListR21 AI100379 / AI / NIAID NIH HHS / United States
AI-065604 / AI / NIAID NIH HHS / United States
AI-100379 / AI / NIAID NIH HHS / United States
DK-38961 / DK / NIDDK NIH HHS / United States