74 - Photoprotective Role of Nrf2 in UVA-Mediated MMP-1 Via MAPK/AP-1 Signaling in Keratinocyte HaCaT Cells and Mouse Skin: The Photoprotective Effects of Sulforaphane

Abstract

Ultraviolet A (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 which can activate Nrf2, a transcription factor regulating antioxidant gene expression, could thus be developed into anti-photoaging agents. We aimed to investigate whether genetic silencing of Nrf2 affected UVA (4 J/cm2)-mediated MMP-1 upregulation through MAPK/AP-1 signaling in immortalized human keratinocyte (HaCaT) cells. Then, we explored the anti-photoaging effects of sulforaphane (SF) having abilities to activate Nrf2 on MMP-1 and collagen expressions in association with phosphorylation of MAPKs (ERK, JNK and p38), c-Jun and c-Fos in the skin of BALB/c mice subjected to repetitive UVA irradiation; three times per week for 2 weeks and the total dose was 60 J/cm2. Our findings revealed that Nrf2 knockdown promoted MMP-1 activity and mRNA levels in UVA-irradiated HaCaT cells. Treatment of Nrf2-depleted HaCaT cells with MAPK inhibitors significantly suppressed MMP-1 and AP-1 transcriptional activity following UVA exposure. Our results also demonstrates the in vivo relevance of the in vitro findings as SF capable of activating Nrf2 provided the protective effects on UVA-mediated MMP-1 induction and collagen depletion in correlation with decreased levels of phosphorylated MAPKs, c-Jun and c-Fos in mouse skin. In conclusion, Nrf2 plays a photoprotective role in UVA-mediated MMP-1 upregulation probably through an involvement of MAPK/AP-1 signaling. Additionally, SF with Nrf2 activating properties could protect against UVA-induced MMP-1 expression through MAPK/AP-1 pathway and may represent promising anti-photoaging candidates.