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Sulfated and Glucuronated trans-Resveratrol Metabolites Regulate Chemokines and Sirtuin-1 expression in U-937 macrophages Katharina Schueller, Marc Pignitter, and Veronika Somoza J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.5b01830 • Publication Date (Web): 25 Jun 2015 Downloaded from http://pubs.acs.org on July 3, 2015
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Journal of Agricultural and Food Chemistry
Reduction of LPS-induced chemokine release in human macrophages 343x218mm (150 x 150 DPI)
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Journal of Agricultural and Food Chemistry
Sulfated and Glucuronated trans-Resveratrol Metabolites Regulate Chemokines and Sirtuin-1 expression in U-937 macrophages
Katharina Schueller *,†, Marc Pignitter *, and Veronika Somoza *,†,1 *
Department of Nutritional and Physiological Chemistry, Faculty of Chemistry, University of
Vienna, Althanstraße 14, 1090 Vienna, Austria †
Christian Doppler Laboratory for Bioactive Aroma Compounds, University of Vienna,
Althanstraße 14, 1090 Vienna Austria 1
Author to whom correspondence should be addressed; E-mail
[email protected];
Phone: +43-4277-70610; Fax: +43-4277-970610.
Short title: Anti-inflammatory effect of resveratrol and metabolites
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Journal of Agricultural and Food Chemistry
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ABSTRACT
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The natural anti-inflammatory compound resveratrol (RES) is metabolized upon ingestion. After
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dietary-scale doses, plasma concentrations of sulfated and glucuronated metabolites in humans exceed
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those of RES. The aim of this in vitro study was to assess the effect of physiological concentrations (1
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µM) of the most abundant RES metabolites (RES-3-O-sulfate, R3S; RES-disulfates, RdS; RES-3-O-
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glucuronide, R3G; RES-4’-O-glucuronide, R4G) on genes and proteins involved in immune cell
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chemotaxis and inflammation (IL-8, MIP-1b, MCP-1, CCR1, CCR2, CXCR2, SIRT1) in a cell model
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of lipopolysaccharide (LPS) activated U-937 macrophages. Levels of MCP-1 mRNA were comparably
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decreased after 3 h treatment with R3S and RdS by -24.7 ± 5.51% and -28.7 ± 19.2%. LPS-induced
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MCP-1 protein release was reduced after 3 h treatment by R3S (-20.8 ± 13.9%) and RdS (-25.7 ±
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8.29%). After a 9 h treatment, RdS also inhibited IL-8 and MIP-1b protein release by -22.9 ± 3.57%
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and -20.1 ± 7.00%. Glucuronides showed differential effects after 6 h of treatment, with R4G up-
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regulating mRNA of MIP-1b (24.5 ± 14.8%), and R3G and R4G down-regulating CXCR2 surface
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protein compared to cells treated with LPS alone, by -5.33 ± 4.18% and -15.2 ± 5.99%, respectively.
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Contrary, R3G and R4G up-regulated SIRT1 mRNA by 22.7 ± 17.9% and 22.8 ± 16.9% in LPS-
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stimulated U-937 macrophages, showing anti-inflammatory properties. In conclusion, sulfated RES
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metabolites show an interesting beneficial potential for attenuating inflammatory immune processes.
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KEYWORDS: resveratrol metabolites, immune cells, macrophages, chemokines, receptors,
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MCP-1
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Journal of Agricultural and Food Chemistry
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INTRODUCTION
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The ameliorating effect of the polyphenol trans-resveratrol (RES) in inflammatory diseases
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has been studied intensively over the last decades.1 RES has been shown to influence
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signaling molecules, enzymes, proteins and transcription factors, by modulating the
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arachidonic acid cascade and the prostaglandin synthesis2,3, among other mechanisms, thus
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counteracting inflammatory processes in vitro.4 However, the beneficial effects of RES in
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vitro must be seen in context to its low bioavailability in vivo. Walle et al.5 measured a
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concentration of
