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J Nutr Biochem. 2014 Jul;25(7):734-40. doi: 10.1016/j.jnutbio.2014.03.005. Epub 2014 Mar 27.

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

Author information

1
Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, CA 94121, USA; Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA.
2
College of Pharmacy, Chungbuk National University, Cheongju 361-763, South Korea.
3
Radiation Research Division, Korea Atomic Energy Research Institute, Jeongeup 580-185, South Korea.
4
Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA; Department of Medicine and Endocrinology, School of Medicine, University of California, San Francisco, San Francisco, CA 94121, USA.
5
Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, CA 94121, USA; Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA. Electronic address: uchiday@derm.ucsf.edu.

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 (ERs) 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 an 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 up-regulation 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.

KEYWORDS:

Cathelicidin antimicrobial peptide; Estrogen receptor β; Genistein; Innate immunity; Keratinocytes

PMID:
24768661
PMCID:
PMC4441818
DOI:
10.1016/j.jnutbio.2014.03.005
[Indexed for MEDLINE]
Free PMC Article
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