The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism.
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.
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.
Kyungho
K
Park
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.
Young-Il
YI
Kim
College of Pharmacy, Chungbuk National University, Cheongju 361-763, South Korea.
Kyong-Oh
KO
Shin
Radiation Research Division, Korea Atomic Energy Research Institute, Jeongeup 580-185, South Korea.
Ho Seong
HS
Seo
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.
Jong Youl
JY
Kim
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.
Taj
T
Mann
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.
Yuko
Y
Oda
College of Pharmacy, Chungbuk National University, Cheongju 361-763, South Korea.
Yong-Moon
YM
Lee
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.
Walter M
WM
Holleran
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.
Peter M
PM
Elias
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.
Yoshikazu
Y
Uchida
D023181:Antimicrobial Cationic Peptides; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D054804:Cathelicidins / Q000096:biosynthesis*; D002478:Cells, Cultured; D055572:Ceramidases / Q000096:biosynthesis; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000502:physiology; D000077267:Fulvestrant; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D008246:Lysophospholipids / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D022763:CCAAT-Enhancer-Binding Protein-alpha; D054804:Cathelicidins; D047629:Estrogen Receptor beta; D008246:Lysophospholipids; D010080:Oxazoles; D010636:Phenols; D018167:Receptors, Calcitriol; C502077:WAY 200070; D000077267:Fulvestrant; C060506:sphingosine 1-phosphate; D004958:Estradiol; D019833:Genistein; D055572:Ceramidases; D013110:Sphingosine
Cathelicidin antimicrobial peptide; Estrogen receptor β; Genistein; Innate immunity; Keratinocytes