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 1-5μM, increased the viability of, and inhibited ROS production in HaCaT cells exposed to UVA irradiation. Pre-treatment of HaCaT 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 Ca(2+) into HaCaT cells and the phosphorylation of Ca(2+)/calmodulin-dependent kinases (CaMKs).


CONCLUSIONS
The results indicate that apigenin and luteolin inhibited UVA-induced collagenolytic MMP-1 production by interfering with Ca(2+)-dependent MAPKs and AP-1 signaling. They may thus be potentially useful in the prevention and treatment of skin photoaging.
Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
Yong Pil
YP
Hwang
Kyo Nyeo
KN
Oh
Hyo Jeong
HJ
Yun
Hye Gwang
HG
Jeong
D047310:Apigenin / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects; D047311:Luteolin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000528:radiation effects; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D047310:Apigenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D047311:Luteolin