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

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, phosphoinositide 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. Conclusion: 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.