Resveratrol Induces Long-Lasting IL-8 Expression and Peculiar EGFR Activation/Distribution in Human Keratinocytes: Mechanisms and Implications for Skin Administration

Abstract

Anti-inflammatory and skin tumour preventing effects of resveratrol have been extensively studied pre-clinically and resveratrol has been proposed for clinical investigations. To provide a basis or/and limitations for topical administration to human skin, molecular mechanisms underlying resveratrol effects towards normal human epidermal keratinocytes (NHEK) were evaluated. NHEK were challenged by either resveratrol alone or by its combination with TNFalpha or TGFalpha, and time-dependent molecular events were monitored. Interleukin 8 (IL-8) expression and its mRNA stability, ERK1/2, p65/RelA, and EGFR phosphorylation were determined. Intracellular distribution of EGFR/P-EGFR was measured in the membrane, cytoplasmic, and nuclear fractions. Specific DNA binding activity of NFκB (p65/RelA) and AP-1(c-Fos), NHEK proliferation, and molecular markers of apoptosis/cell cycle were detected. Resveratrol induced delayed, long-lasting and steadily growing IL-8 gene and protein over-expression as well as enhanced EGFR phosphorylation, both abrogated by the EGFR kinase inhibitor PD168393. However, resveratrol did not act as a phosphatase inhibitor. ERK phosphorylation was transiently inhibited at early time-points and activated at 6–24 h. Accordingly, c-Fos-specific DNA binding was increased by resveratrol. Cellular distribution of EGFR/P-EGFR was shifted to membrane and nucleus while cytosolic levels were reduced concomitant with enhanced degradation. Notwithstanding high nuclear levels of EGFR/P-EGFR, spontaneous and TGFalpha-triggered cell proliferation was strongly suppressed by resveratrol mainly through cell cycle arrest.Conclusions/SignificanceResveratrol synergized with TNFα in the induction of delayed, long-lasting IL-8 expression through sustained EGFR-ERK axis activation. The time course indicates that resveratrol metabolites could be implicated. Topical administration of Resv to psoriatic patients over-expressing TNFα, IL-8 and EGFR-ERK in the skin should be cautiously considered. Since high nuclear levels of EGFR correspond to increased risk of tumorigenesis, chronic resveratrol application to the skin may be potentially dangerous. Wound healing acceleration by resveratrol could not be envisaged due to its anti-proliferative effects towards normal keratinocytes.

Effects of supplementation of medium with different antioxidants during in vitro maturation of bovine oocytes on subsequent embryo production

“…Even though the new compounds formed from the oxidation of the antioxidants (quercetin–quinone, resveratrol–quinone, dehydroascorbic acid) are less harmful than ROS, they are still reactive and can interact with thiol compounds such as reduced GSH. The new compounds formed from the oxidation of antioxidants were probably recycled through GSH and converted back into the original compounds (quercetin, resveratrol or vitamin C) and due to this mechanism of GSH consumption during the recycling process, there was not an increase in GSH levels in oocytes matured in vitro with these antioxidants (Boots et al., ; Kim & Jang, ; Li, Qu, & May, ; May, Qu, & Li, ; May, Qu, & Morrow, ; Pastore et al., ).…”

Secondary Plant Metabolites for Sun Protective Cosmetics: From Pre-Selection to Product Formulation

“…Theoretically, SPMs could modify skin-UV interaction at several crucial points: (a) by absorption of UVA + UVB (screen action); (b) by inhibition of UV-induced free radical reactions in skin cells and extracellular matrix (scavenging and direct antioxidant chain-breaking effects); (c) by protection of skin surface lipid antioxidants, such as alpha-tocopherol, coenzyme Q10, and squalene (antioxidant rescue action); (d) by induction of endogenous antioxidant systems in keratinocytes and fibroblasts (indirect antioxidant effects); (e) by attenuation of inflammatory responses in cutaneous immune cells (keratinocytes/leukocytes/dendritic cells); (f) by modulation of excessive metabolic and proliferative UV-induced stress responses (anti-stress effects), and (g) by attenuation of UV-related immune suppression (immuno-modulation) [23,[78][79][80].…”

Transcriptome‐Based Analysis in Lactobacillus plantarum WCFS1 Reveals New Insights into Resveratrol Effects at System Level

“…RSV has been reported to mediate DNA breakage . However, the genotoxic activity of RSV is totally dependent on the presence of copper ions which act as reactants to generate reactive oxygen species from RSV (mainly O 2 − and H 2 O 2 ) via a Fenton‐like reaction which provokes oxidative DNA lesions.…”