Phospholipid-hydroperoxide glutathione peroxidase (PHGPx) exhibits high specific activity in reducing
phosphatidylcholine hydroperoxides (PCOOHs) and thus may play a central role in protecting the skin against UV irradiation-triggered detrimental long term effects like
cancer formation and premature skin aging. Here we addressed the role of PHGPx in the protection against UV irradiation-induced expression of
matrix metalloproteinase-1 (MMP-1). For this purpose, we created human dermal fibroblast cell lines overexpressing human PHGPx. Overexpression led to a significant increase in PHGPx activity. In contrast to a maximal 4.5-fold induction of specific MMP-1
mRNA levels in vector-transfected cells at 24 h after UVA irradiation, no MMP-1 induction occurred at any studied time point after UVA treatment of PHGPx-overexpressing fibroblasts. As
interleukin-6 (IL-6) was earlier shown to mediate the UVA induction of MMP-1, we studied whether PHGPx overexpression might interfere with the NFkappaB-mediated
IL-6 induction and downstream signaling. Using transient transfections of
IL-6 promoter constructs containing NFkappaB binding sites, we observed a high induction of the reporter gene
luciferase in vector-transfected control cells and a significantly lower induction in PHGPx-overexpressing fibroblasts following UVA irradiation. Consistently both UVA irradiation and treatment of fibroblasts with PCOOHs led to phosphorylation and nuclear translocation of the p65 subunit, whereas cells overexpressing PHGPx exhibited impaired NFkappaB activation, p65 phosphorylation, and nuclear translocation. In line with this, the PHGPx-overexpressing fibroblasts showed a reduced constitutive and UVA irradiation-induced
IL-6 release. After incubating PHGPx-overexpressing cells with PCOOHs a reduced induction of
IL-6 was observed. This together with the suppression of UVA irradiation-induced
IL-6 release in the presence of
Trolox, a chain breaker of
PCOOH-initiated lipid peroxidation, indicates that UVA irradiation-induced PCOOHs and subsequent
lipid peroxides initiate the NFkappaB-mediated induction of
IL-6, which mediates the induction of MMP-1. Our finding is particularly relevant in light of the already available small molecule mimetics of PHGPx.