Abstract
UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates.
Highlights
Exposure of the skin to UV radiation is the primary cause of premature skin aging, which is a multifactorial process involving various molecular pathways (Baumann, 2007; Hwang et al, 2011a; Panich et al, 2016)
Depletion of Nuclear factor E2-related factor 2 (Nrf2) Augmented UVA-Induced matrix metalloproteinase-1 (MMP-1) via Modulation of mitogenactivated protein kinase (MAPK)/activator protein-1 (AP-1) Signaling in Keratinocyte human keratinocyte (HaCaT) Cells
We previously reported that UVA caused MMP-1 upregulation through induction of oxidative stress and depletion of antioxidant defenses in HaCaT cells (Pluemsamran et al, 2012, 2013)
Summary
Exposure of the skin to UV radiation is the primary cause of premature skin aging, which is a multifactorial process involving various molecular pathways (Baumann, 2007; Hwang et al, 2011a; Panich et al, 2016). Oxidative stress mediated by UVA radiation has been suggested to play a vital role in the induction of MMP-1 produced. Nuclear factor E2-related factor 2 (Nrf2), the redoxsensitive transcription factor, is a master regulator of the cellular antioxidant defense against environmental insults, including UV radiation. Nrf has been reported to play a beneficial role in protecting skin cells, including keratinocytes, fibroblasts, and melanocytes, against UV-induced oxidative damage and cellular dysfunction (Seo et al, 2011; Brugè et al, 2014; Gegotek and Skrzydlewska, 2015). Investigation of compounds targeting Nrf2-regulated antioxidant defense to combat oxidative stress could provide insight into development of a promising pharmacological approach to help delay skin photoaging. It has been shown that the transcriptional regulation of MMP-1 is mediated by activation of activator protein-1 (AP-1) and its upstream mitogen-activated
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