Abstract
The present study was intended to explore the effects of endogenously produced ω-3 polyunsaturated fatty acids (PUFAs) on ultraviolet B (UVB)-induced skin inflammation and photocarcinogenesis using hairless fat-1 transgenic mice harboring ω-3 desaturase gene capable of converting ω-6 to ω-3 PUFAs. Upon exposure to UVB irradiation, fat-1 transgenic mice exhibited a significantly reduced epidermal hyperplasia, oxidative skin damage, and photocarcinogenesis as compared to wild type mice. The transcription factor, Nrf2 is a master regulator of anti-inflammatory and antioxidant gene expression. While the protein expression of Nrf2 was markedly enhanced, the level of its mRNA transcript was barely changed in the fat-1 transgenic mouse skin. Topical application of docosahexaenoic acid (DHA), a representative ω-3 PUFA, in wild type hairless mice induced expression of the Nrf2 target protein, heme oxygenase-1 in the skin and protected against UVB-induced oxidative stress, inflammation and papillomagenesis. Furthermore, transient overexpression of fat-1 gene in mouse epidermal JB6 cells resulted in the enhanced accumulation of Nrf2 protein. Likewise, DHA treated to JB6 cells inhibited Nrf2 ubiquitination and stabilized it. Taken together, our results indicate that functional fat-1 and topically applied DHA potentiate cellular defense against UVB-induced skin inflammation and photocarcinogenesis through elevated activation of Nrf2 and upregulation of cytoprotective gene expression.
Highlights
Exposure of skin to excessive ultraviolet B (UVB) causes the production of reactive oxygen species (ROS), which results in massive infiltration of inflammatory cells, especially, neutrophils at the site of tissue injury[6]
To avoid the inconvenience of frequent hair removal in determining whether an increased ω-3 polyunsaturated fatty acids (PUFAs) tissue accumulation in fat-1 mice is protective against skin carcinogenesis induced by repeated UVB irradiation, we generated hairless fat-1 mice by crossing fat-1+/− haired and SKH-1 hairless mice (Fig. 1A)
Mounting evidence from epidemiological and laboratory-based studies suggest that long chain ω-3 PUFAs possess a broad range of health beneficial properties[16] and exert protective effects against oxidative stress-induced inflammation[32], aging[33], cancer[34], etc
Summary
Exposure of skin to excessive ultraviolet B (UVB) causes the production of reactive oxygen species (ROS), which results in massive infiltration of inflammatory cells, especially, neutrophils at the site of tissue injury[6]. Kang et al developed genetically engineered mice of C57BL6 background carrying a fat-1 gene which encodes an ω-3 fatty acid desaturase derived from Caenorhabditis elegans[22,23]. These transgenic mice are capable of converting ω-3 PUFAs from ω-6 PUFAs, thereby maintaining a significantly elevated ω-3/ω-6 PUFA ratio in their tissues and organs. Hairless fat-1 transgenic mice were generated by cross-breeding of male fat-1+/− mice with female SKH-1 hairless mice By utilizing these hairless fat-1 transgenic mice maintained on ω-6 PUFA containing diet, we investigated the effect of endogenously formed ω-3 PUFAs on the development of UVB-induced tumors as well as oxidative stress and inflammation in the skin
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