The flavonoids apigenin and luteolin suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and AP-1-dependent signaling in HaCaT cells

Background: Ultraviolet (UV) irradiation causes major changes in skin connective tissues as a result of the degradation of collagen, a major structural component of the extracellular matrix. This process is likely mediated by matrix metalloproteinases (MMPs). Such changes in collagenous skin tissues have been suggested to be causes of cutaneous aging and skin cancer. Objective: We investigated the protective effects of apigenin and luteolin on immortalized human keratinocytes (HaCaT) against UVA damage. We then explored the inhibitory effects of apigenin and luteolin on UVA-induced MMP-1 and investigated the molecular mechanism underlying those effects. Methods: HaCaT cells were treated with apigenin and luteolin for the indicated times followed by irradiation with UVA. Those effects were assessed by semi-quantitative PCR, Western blotting and enzymic activity assays. Results: These two compounds, at concentrations of 1-5 mu M, increased the viability of, and inhibited ROS production in HaCaT cells exposed to UVA irradiation. Pre-treatment of HaCa'T cells with apigenin and luteolin also inhibited UVA-induced production of the collagenases MMP-1. They also suppressed UVA-induced expression of c-Jun and c-Fos and the phosphorylation of three MAP kinases, upstream modulators of AP-1. Furthermore, the same two flavonoids decreased the UVA-induced influx of Ca2+ into HaCaT cells and the phosphorylation of Ca2+/calmodulin-dependent kinases (CaMKs). Conclusion: The results indicate that apigenin and luteolin inhibited UVA-induced collagenolytic MMP-1 production by interfering with Ca2+-dependent MAPKs and AP-1 signaling. They may thus be potentially useful in the prevention and treatment of skin photoaging. (c) 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.