title: Resveratrol stimulates sphingosine-1-phosphate signaling of cathelicidin production.
abstract: We recently discovered a regulatory mechanism that stimulates the production of the multifunctional antimicrobial peptide cathelicidin antimicrobial peptide (CAMP). In response to subtoxic levels of ER stress, increased sphingosine-1-phosphate (S1P) production activates an NFκBC/EBPα-dependent pathway that enhances CAMP production in cultured human keratinocytes. As the multifunctional stilbenoid compound resveratrol (RESV) increases ceramide (Cer) levels, a precursor of S1P, we hypothesized and assessed whether RESV could exploit the same pathway to regulate CAMP production. Accordingly, RESV significantly increased Cer and S1P levels in cultured keratinocytes, paralleled by increased CAMP mRNA/protein expression. Furthermore, topical RESV also increased murine CAMP mRNA/protein expression in mouse skin. Conversely, blockade of Cer-->sphingosine-->S1P metabolic conversion, with specific inhibitors of ceramidase or sphingosine kinase, attenuated the expected RESV-mediated increase in CAMP expression. The RESV-induced increase in CAMP expression required both NF-κB and C/EBPα transactivation. Moreover, conditioned media from keratinocytes treated with RESV significantly suppressed Staphylococcus aureus growth. Finally, topical RESV, if not coapplied with a specific inhibitor of sphingosine kinase, blocked S. aureus invasion into murine skin. These results demonstrate that the dietary stilbenoid RESV stimulates S1P signaling of CAMP production through an NF-κB-->C/EBPα-dependent mechanism, leading to enhanced antimicrobial defense against exogenous microbial pathogens.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Park
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Borkowski
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Kyong-Oh
authors.initials: KO
authors.lastname: Shin
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D000975:Antioxidants / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D054804:Cathelicidins / Q000276:immunology / Q000378:metabolism*; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008812:Mice, Hairless; D016328:NF-kappa B / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013207:Staphylococcal Skin Infections / Q000188:drug therapy / Q000276:immunology; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D023181:Antimicrobial Cationic Peptides; D000975:Antioxidants; D022763:CCAAT-Enhancer-Binding Protein-alpha; D054804:Cathelicidins; D008246:Lysophospholipids; D016328:NF-kappa B; D013267:Stilbenes; C060506:sphingosine 1-phosphate; D000242:Cyclic AMP; D013110:Sphingosine; D000077185:Resveratrol