Kyungho Park, Peter M. Elias, Melanie Hupe, Andrew W

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Resveratrol Stimulates Sphingosine-1-Phosphate Signaling of Cathelicidin Production Kyungho Park, Peter M. Elias, Melanie Hupe, Andrew W. Borkowski, Richard L. Gallo, Kyong-Oh Shin, Yong-Moon Lee, Walter M. Holleran, Yoshikazu Uchida Journal of Investigative Dermatology Volume 133, Issue 8, Pages 1942-1949 (August 2013) DOI: 10.1038/jid.2013.133 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Resveratrol (RESV)-mediated increase in sphingosine-1-phosphate (S1P) is responsible for the stimulation of cathelicidin antimicrobial peptide (CAMP) expression. HaCaT keratinocytes (KCs) pretreated with or without ceramidase (N-oleoylethanolamine (NOE), 25μM) or SPHK (dimethylsphingosine (DMS), 2.5μM; SKI, 1μM) inhibitors for 30 minutes were incubated with exogenous RESV (50μM or as indicated) for 24 hours. Cell viability (a) or poly(ADP-ribose) polymerase (PARP) cleavage as a measure of apoptosis (b). CAMP mRNA expression assessed by quantitative real-time (qRT–PCR) (c and d). CAMP and LL-37 (an active form of CAMP) protein/peptide levels quantified by western immunoblot analysis (e) and ELISA, respectively (f and g). Similar results were obtained when the experiment was repeated (triplicate) using different cell preparations. Journal of Investigative Dermatology 2013 133, 1942-1949DOI: (10.1038/jid.2013.133) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Topical resveratrol (RESV) increases murine CAMP (mCAMP) expression in normal murine skin. The flanks of mice were treated with topical applications of RESV or vehicle (ethanol) alone. Hematoxylin and eosin (H&E) staining (a). Epidermal thickness (b). mCAMP mRNA (c) and protein expression (d). Similar results were obtained when the experiment was repeated (in duplicate) using different skin preparations. Bar=20μm. Journal of Investigative Dermatology 2013 133, 1942-1949DOI: (10.1038/jid.2013.133) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 NF-κB-C/EBPα activation is required for resveratrol (RESV)-induced upregulation of cathelicidin antimicrobial peptide (CAMP) expression. HaCaT keratinocytes (KCs) were pretreated or transfected with/without a specific inhibitor of SPHK1, SKI (1μM), NF-κB inhibitor (BAY11-7082, 2μM), mitogen-activated protein (MAP) kinase inhibitors ((U0126, ERK inhibitor), SB (SB201290, p38MAP kinase inhibitor)), or SPHK1-siRNA, followed by incubation with RESV (50μM). Phosphorylated forms of NF-κB or C/EBPα (either Ser-21 or Thr-222/226) in nuclear fractions were assessed by western immunoblot analysis (a and e). RESV-induced nuclear translocation of NF-κB was determined by immunohistochemistry (b). NF-κB transactivation was assessed using a luciferase reporter assay (c). CAMP mRNA (d and f). Similar results were obtained when the experiment was repeated (duplicate) using different cell preparations. Bar=30μm. Journal of Investigative Dermatology 2013 133, 1942-1949DOI: (10.1038/jid.2013.133) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Resveratrol (RESV) enhanced antimicrobial defense through increased cathelicidin antimicrobial peptide (CAMP) production. Growth inhibition of S. aureus. S. aureus strain were incubated for the indicated times with LL-37 or conditioned medium of HaCaT keratinocytes (KCs) treated with RESV (50μM) (a). Bacterial invasion studies (ex vivo) (b and c): S. aureus strain were epicutaneously applied to full-thickness pieces of murine skin (n=2) treated with RESV (50mM (250nmolecm−2)), SKI (1μM), LL-37 RESV (50μM (250pmolecm−2)), and/or vehicle twice daily for 3 days, followed by incubation for 24 hours at 37°C. CAMP mRNA expression in skin was assessed by quantitative real-time (qRT–PCR) (b). Bacterial invasion/growth into murine skin was assessed by Gram staining (counterstaining with hematoxylin and eosin) (c). Scale bar=50μm. Journal of Investigative Dermatology 2013 133, 1942-1949DOI: (10.1038/jid.2013.133) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Proposed mechanism of resveratrol (RESV)-mediated stimulation of cathelicidin antimicrobial peptide (CAMP) production in keratinocytes (KCs). RESV stimulates cellular ceramide (Cer) production and also increases Cer metabolic conversion to sphingosine and then SIP by SPHKI (but not SPHK2). SIP activates NF-κB-phosphorylation, leading to the translocation of phospho-NF-κB to the nucleus. NF-κB increases p38 mitogen-activated protein (p38MAP) kinase activation that stimulates C/EBPα by its phosphorylation of Thr-222/226, rather than Ser-21 sites. C/EBPα binds to the 5′-upstream promoter region of CAMP to upregulate CAMP expression. RESV also stimulates CAMP/LL-37 secretion from cells, resulting in enhanced antimicrobial defense in the epidermis. Journal of Investigative Dermatology 2013 133, 1942-1949DOI: (10.1038/jid.2013.133) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions