Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production

Abstract

The steroid hormone metabolite of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25D3), promotes osteogenic activity and regulates calcium and phosphate metabolism, which are actions regarded as classical vitamin D-regulated functions. Besides its role in these processes, 1,25D3 also seems implicated in the host defense against microbial/proinflammatory attacks. Low serum levels of vitamin D 3 (vitamin D deficiency) are associated with osteoporosis and increased risk of fractures but also inflammatory diseases and their disease progression, presumably via mechanisms associated with 1,25D3-evoked modulation of the innate immune system. 1,25D3 has been reported to modulate many inflammatory responses, suggesting that it regulates multiple transcriptional targets within the inflammatory system. Experimental studies in various experimental systems show that 1,25D3 differentially regulates the production of pro-inflammatory cytokines and chemokines depending on cell type. Importantly, many reports show that 1,25D3 up-regulates expression of the human antimicrobial peptide hCAP-18/LL-37 gene. The hCAP-18/LL-37 gene seems indeed to be an important transcriptional target for 1,25D3. However, only weak evidence is presented showing that 1,25D3 consistently increases the amount of biologically active LL-37 peptide.In the present review, we discuss 1,25D3-induced down-regulation of cytokine/chemokine production and stimulation of hCAP-18/LL-37 gene expression which represent two very important pathways for 1,25D3-evoked regulation of the innate immune response.

DNA methylation directly downregulates human cathelicidin antimicrobial peptide gene (CAMP) promoter activity

“…The transcriptional regulation by human CAMP promoter has widely been reported [8–11]. Our bioinformatics analysis using CpGplot program indicated that the human CAMP promoter is not located within CpG islands (http://www.ebi.ac.uk/Tools/seqstats/emboss_cpgplot/).…”

“…Human CAMP expression can be downregulated by Bacterial exotoxins, Shigella infection, Psychological stress or Calcipotriol [3, 4]. Transcription factors that can regulate human CAMP gene expression include cAMP-responsive element-binding protein (CREB) [3], Hypoxia inducible factor-1 (HIF-1) [4], Vitamin D receptor (VDR) [8], CCAAT enhancer binding protein α (C/EBPα) [9], activator protein 1(AP-1) [10] and C/EBPβ [11]. ER stress increases CAMP expression via NF-κB-C/EBPα activation, independent of VDR pathway [9].…”

“…In recent years it has been shown that DNA methylation at CpG sites in non-CpG island promoters can also contribute to regulate gene expression [12, 15–18]. Studies on transcriptional regulation of human CAMP have been widely reported [3–11]. However, detailed mechanism about how DNA methylation regulates human CAMP expression remains unclear.…”

Vitamin D-induced up-regulation of human keratinocyte cathelicidin anti-microbial peptide expression involves retinoid X receptor α

“…Indeed, we show here that both CAMP gene activity and the hCAP-18 protein level are enhanced in human keratinocytes in response to stimulation with 1,25D3. LL-37 is suggested to exert its anti-microbial activity through multiple mechanisms including the permeabilization of the bacterial cell wall, the neutralization of bacterial lipopolysaccharide, and the stimulation of chemokine production, but, additionally, LL-37 might seriously reduce host cell viability (Burton and Steel 2009;Säll et al 2013;Svensson et al 2016a). In patients suffering from chronic periodontitis, ulcerative colitis and rosacea micromolar concentrations of LL-37 are observed locally, and in lesions from patients suffering from psoriasis, the LL-37 concentration can exceed the several hundred micromolar level (Türkoğlu et al 2009;Ong et al 2002;Schauber et al 2006;Yamasaki et al 2007).…”

Host Defense Peptide Expression in Human Cervical Cells and Regulation by 1,25-Dihydroxyvitamin D3 in the Presence of Cytokines and Bacterial Endotoxin

“…Pro-inflammatory cytokines, neutrophil proteases, microbial endotoxins 7, 12 steroids 13,14 and vitamin D 12,[15][16][17] have been shown to upregulate a variety of HDPs in vitro.…”