Biological Mechanisms Underlying the Ultraviolet Radiation-Induced Formation of Skin Wrinkling and Sagging: Over-Expression of Fibroblast Elastase Neprilysin Plays an Essential Role in Reduced Skin Elasticity as Its Causative Physical Property

The repetitive exposure of skin to ultraviolet B (UVB) preferentially elicits wrinkling while ultraviolet A
(UVA) predominantly elicits sagging. In chronically UVB or UVA-exposed rat skin there is a similar
tortuous deformation of elastic fibers together with decreased skin elasticity, whose magnitudes are
greater in UVB-exposed skin than in UVA-exposed skin. Comparison of skin elasticity with the activity
of matrix metalloproteinases (MMPs) in the dermis of ovariectomized rats after UVB or UVA irradiation
demonstrates that skin elasticity is more significantly decreased in ovariectomized rats than in shamoperated
rats, which is accompanied by a reciprocal increase in elastase activity but not in the
activities of collagenases I or IV. Clinical studies using animal skin and human facial skin
demonstrated that topical treatment with a specific inhibitor or an inhibitory extract of skin fibroblastderived
elastase distinctly attenuates UVB and sunlight-induced formation of wrinkling. Our results
strongly indicated that the upregulated activity of skin fibroblast-derived elastase plays a pivotal role in
wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the
subsequent loss of skin elasticity. Fortunately, we succeeded in identifying human skin fibroblastderived
elastase as a previously known enzyme, neprilysin or neutral endopeptidase (NEP). Using
information on the gene of and antibody to neprilysin, we have characterized epithelial–mesenchymal
paracrine cytokine interactions between UVB-exposed-keratinocytes and dermal fibroblasts and found
that interleukin-1α and granulocyte macrophage colony stimulatory factor (GM-CSF) are intrinsic
cytokines secreted by UVB-exposed keratinocytes that stimulate the expression of neprilysin by
fibroblasts. On the other hand, direct UVA exposure of human fibroblasts significantly stimulates the
secretion of IL-6 and also elicits a significant increase in the gene expression of matrix metalloprotease
(MMP)-1 as well as neprilysin (to a lesser extent), which is followed by distinct increases in
their protein and enzymatic activity levels. Direct UVA exposure of human keratinocytes also
stimulates the secretion of IL-6, IL-8 and GM-CSF but not of IL-1 and endothelin-1. These findings
suggest that GM-CSF secreted by UVA-exposed keratinocytes as well as IL-6 secreted by UVAexposed
dermal fibroblasts play important and additional roles in UVA-induced sagging and wrinkling
by up-regulation of neprilysin and MMP-1, respectively, in dermal fibroblasts.