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.

MicroRNA-939 restricts Hepatitis B virus by targeting Jmjd3-mediated and C/EBPα-coordinated chromatin remodeling

“…Several reports suggested that Jmjd3 plays a role in general chromatin remodeling28 via interaction with an ATPase subunit of the SWI/SNF chromatin remodeling complex, Brg12829 and this interaction occurs in histone demethylase-independent manner. Moreover, the interaction between C/EBPα and SWI/SNF complex has also been described30313233. Indeed, we found that both Brm and Brg1 exhibited a promoting effect on HBV transcription (Fig.…”

“…Human SWI/SNF complexes, required for a wide variety of transcriptional programs during development, consist of ~15 subunits and contain Brg1 or Brm exclusively as the ATPase subunits454647. Moreover, the physical and functional interaction between C/EBPα and SWI/SNF complexes had also been documented303248. In hepatocytes, the ATPase subunit of SWI/SNF complex, i.e.…”

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

“…18,29 Notably, these pathways are involved in enhanced expression of LL-37. 30,31 Here, we have demonstrated that LL-37-mediated autophagy requires intracellular calcium influx together with the signaling pathways AMPK and PtdIns3K downstream of the P2RX7 receptor. Together with calcium mobilization, these pathways are essential for the induction of the autophagy process in macrophages.…”

LL-37 disrupts the Kaposi's sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells

“…While LL-37 exerts its antiviral activity via a direct effect on the virion in the case of this paper and others, cathelicidins in general (He et al, 2018) and LL-37 specifically (Barlow et al, 2014a) have also been shown to enhance other methods of innate antiviral immunity, namely interferon expression. Current work in endogenous antimicrobial peptide expression (Dhawan et al, 2015; Klein-Patel et al, 2006; Rivas-Santiago et al, 2005; Ryan et al, 2011; Ryan and Diamond, 2017) and small molecule mimetics of antimicrobial peptides (Beckloff et al, 2007; Menzel et al, 2017; Ryan et al, 2014) would potentially serve as methods to prevent not only KSHV infection, but also other viral infections of the oral cavity.…”