Abstract
A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 (MMP‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB‐induced MMP‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm2) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB‐induced MMP‐1 expression and AP‐1 activity, and strongly suppressed UVB‐induced phosphorylation of Fos‐related antigen (FRA)‐1 at Ser265. Importantly, UVB irradiation‐induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB‐induced extracellular signal‐regulated kinase 2 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90RSK by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB‐induced wrinkle formation, trans‐epidermal water loss and MMP‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.
Highlights
Epidemiological evidence and molecular studies suggest that exposure of the skin to ultraviolet (UV) light can induce photoaging [1,2,3,4,5]
Because extracellular signalregulated kinase (ERK) signalling is a major regulator of Fos-related antigen 1 (FRA1) [7, 8, 24], we investigated the possibility that naringenin could affect ERKs signalling
We found that naringenin attenuated UVB-induced FRA1 expression (Fig. 2B), whereas the phosphorylation and expression of c-Jun were not affected (Fig. 2A)
Summary
Epidemiological evidence and molecular studies suggest that exposure of the skin to ultraviolet (UV) light (i.e. sunlight) can induce photoaging [1,2,3,4,5]. Photoaged skin is biochemically characterized by a dramatic decrease in collagen and increases in matrix metalloproteinase-1 (MMP-1), or interstitial collagenase, which is considered the major collagenase involved in photoaging in response to UV irradiation [3]. Chronic exposure of the skin to UV, causes abnormal MMP-1 expression [1]. The results of an earlier study have shown that low-dose UV irradiation can induce MMP-1 and wrinkle formation, and inhibition of MMP-1 expression by the downregulation of AP-1 with all-trans retinoic acid (ATRA) prevents UVB-induced photoaging [1]
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