Synergistic induction of human cathelicidin antimicrobial peptide gene expression by vitamin D and stilbenoids

Abstract

Scope The cathelicidin antimicrobial peptide (CAMP) gene is induced by 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), lithocholic acid, curcumin, nicotinamide and butyrate. Discovering additional small molecules that regulate its expression will identify new molecular mechanisms involved in CAMP regulation and increase understanding of how diet and nutrition can improve immune function. Methods and results We discovered that two stilbenoids, resveratrol and pterostilbene, induced CAMP promoter-luciferase expression. Synergistic activation was observed when either stilbenoid was combined with 1α,25(OH)2D3. Both stilbenoids increased CAMP mRNA and protein levels in the monocyte cell line U937 and synergy was observed in both U937 and the keratinocyte cell line, HaCaT. Inhibition of resveratrol targets sirtuin-1, cyclic AMP production and the c-Jun N-terminal, phophoinositide 3 and AMP-activated kinases did not block induction of CAMP by resveratrol or synergy with 1α,25(OH)2D3. Nevertheless, inhibition of the extracellular signal-regulated 1/2 and p38 mitogen-activated protein kinases, increased CAMP gene expression in combination with 1α,25(OH)2D3 suggesting that inhibition of these kinases by resveratrol may explain, in part, its synergy with vitamin D. Conclusions Our findings demonstrate for the first time that stilbenoid compounds may have the potential to boost the innate immune response by increasing CAMP gene expression particularly in combination with 1α,25(OH)2D3.

SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via vitamin D receptor deacetylation

“…Based on the evolutionarily-conserved nature of the steroid and nuclear receptor superfamily and the structural similarity that exists amongst resveratrol and other low-affinity, lipophilic VDR ligands, resveratrol was previously postulated and demonstrated experimentally by Guo and colleagues [43] to modulate intracellular VDR signaling. Independent investigations conducted by Jurutka and coworkers [26], as well as Dampf Stone and collaborators [7] revealed that resveratrol serves as an indirect modifier of the 1,25D-VDR signal transduction cascade, rather than serving as a direct VDR ligand.…”

Virtual screening of a milk peptide database for the identification of food‐derived antimicrobial peptides

“…In addition to synergistic effects, naturally occurring antimicrobial or immunomodulatory milk peptides may have an additional protective effect . Furthermore, the vitamin D content of milk may also be able to induce the expression of human antimicrobial peptides (AMPs) . In the past, a growing number of AMPs has been described, which are encrypted in the milk protein sequence, but released during fermentation or protein hydrolysis .…”

The role of vitamin D in reducing gastrointestinal disease risk and assessment of individual dietary intake needs: Focus on genetic and genomic technologies

“…The evidence for the role of vitamin D in controlling the composition and activity of the gut microbiota may initially appear counter-intuitive. Guo et al [28] demonstrated that vitamin D regulates expression of an antimicrobial peptide, leading to the suggestion of using vitamin D to control bacterial diseases [29]. Secondary bile acids are made by intestinal bacteria, [30] and VDR is a receptor for the secondary bile acid lithocholic acid (LCA) which is hepatotoxic and a possible enteric cancer causing agent [31,32].…”