The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism

Abstract

We recently discovered that a signaling lipid, sphingosine-1-phosphate (S1P), generated by sphingosine kinase 1, regulates a major epidermal antimicrobial peptide’s [cathelicidin antimicrobial peptide (CAMP)] expression via an NF-κB→C/EBPα-dependent pathway, independent of vitamin D receptor (VDR) in epithelial cells. Activation of estrogen receptors (ER) by either estrogens or phytoestrogens also is known to stimulate S1P production, but it is unknown whether ER activation increases CAMP production. We investigated whether a phytoestrogen, genistein, simulates CAMP expression in keratinocytes, a model of epithelial cells, by either a S1P-dependent mechanism(s) or the alternate VDR-regulated pathway. Exogenous genistein, as well as a ER-β ligand, WAY-200070, increased CAMP mRNA and protein expression in cultured human keratinocytes, while ER-β antagonist, ICI182780, attenuated the expected genistein- and WAY-200070-induced increase in CAMP mRNA/protein expression. Genistein treatment increased acidic and alkaline ceramidase expression and cellular S1P levels in parallel with increased S1P lyase inhibition, accounting for increased CAMP production. In contrast, siRNA against VDR did not alter genistein-mediated upregulation of CAMP. Taken together, genistein induces CAMP production via an ER-β→S1P→NF-κB→C/EBPα-rather than a VDR-dependent mechanism, illuminating a new role for estrogens in the regulation of epithelial innate immunity and pointing to potential additional benefits of dietary genistein in enhancing cutaneous antimicrobial defense.

Phytoestrogens as Pharma Foods

“…33 It has been reported that phytoestrogens such as genistein may help to prevent photo aging in human skin and promote formation of hyaluronic acid. 34 …”

Boosting innate immunity: Development and validation of a cell-based screening assay to identify LL-37 inducers

“…Some TFs, however, need an endogenous or exogenous ligand to induce binding/transcription. These are called nuclear receptors and several of them seem to be essential for CAMP gene expression (paper IV) (Gombart et al, 2005;Kulkarni et al, 2016;Park et al, 2014).…”

Sphingosine kinase 1 activation enhances epidermal innate immunity through sphingosine-1-phosphate stimulation of cathelicidin production

“…Accordingly, we recently demonstrated that low levels of endoplasmic reticulum (ER) stress increase cellular S1P levels, directly stimulating production of a key innate immune element, CAMP [8]. We also demonstrated that stimulation of CAMP production could also be enhanced through provision of the S1P precursor, ceramide, or suppression of S1P lyase activity, a S1P degrading enzyme, using naturally-occurring small molecules [14, 26]. For example, we recently demonstrated that the naturally-occurring stilbenoid, resveratrol, and the isoflavone genistein stimulate S1P-signaled CAMP production [14, 26].…”

“…We also demonstrated that stimulation of CAMP production could also be enhanced through provision of the S1P precursor, ceramide, or suppression of S1P lyase activity, a S1P degrading enzyme, using naturally-occurring small molecules [14, 26]. For example, we recently demonstrated that the naturally-occurring stilbenoid, resveratrol, and the isoflavone genistein stimulate S1P-signaled CAMP production [14, 26]. While the former stimulates production of ceramide, the latter inhibits S1P lyase activity, as well as also increasing acidic- and neutral ceramidase activity production, resulting in elevated cellular S1P levels.…”