LL-37, the only known human cathelicidin which is encoded by the human antimicrobial peptide (CAMP) gene, plays a critical role in protection against bacterial infection. We previously demonstrated that cathelicidin is induced by 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) in human airway epithelial cells with a resultant increase in bactericidal activity. In this study we identify key factors that cooperate with 1,25(OH) 2D 3 in the regulation of CAMP. Our results show for the first time that PU.1, the myeloid transcription factor (which has also been identified in lung epithelial cells), cooperates with the vitamin D receptor and C/EBPα to enhance the induction of CAMP in lung epithelial cells. Our findings also indicate that enhancement of 1,25(OH) 2D 3 regulation of CAMP by histone deacetylase inhibitors involves cooperation between acetylation and chromatin remodeling through BRG1 (a component of the SWI/SNF complex). BRG1 can be an activator or repressor depending on BRG1 associated factors. PRMT5, a methlytransferase which interacts with BRG1, represses 1,25(OH) 2D 3 induced CAMP in part through dimethylation of H4R3. Our findings identify key mediators involved in the regulation of CAMP gene in lung epithelial cells and suggest new approaches for therapeutic manipulation of gene expression in order to increase the antibacterial capability of the airway.