Abstract
We recently reported that the over-expression of skin fibroblast-derived neutral endopeptidase (NEP) plays a pivotal role in impairing the three-dimensional architecture of dermal elastic fibers during the biological mechanism of ultraviolet (UV)-induced skin wrinkling. In that process, a UVB-associated epithelial-mesenchymal cytokine interaction as well as a direct UVA-induced cellular stimulation are associated with the up-regulation of NEP in human fibroblasts. In this study, we characterized the mode of action of ubiquinol10 which may abrogate the up-regulation of NEP by dermal fibroblasts, resulting in a reported in vivo anti-wrinkling action, and compared that with 3 other anti-oxidants, astaxanthin (AX), riboflavin (RF) and flavin mononucleotide (FMN). Post-irradiation treatment with all 4 of those anti-oxidants elicited an interrupting effect on the UVB-associated epithelial-mesenchymal cytokine interaction leading to the up-regulation of NEP in human fibroblasts but with different modes of action. While AX mainly served as an inhibitor of the secretion of wrinkle-inducing cytokines, such as interleukin-1α (IL-1α) and granulocyte macrophage colony stimulatory factor (GM-CSF) in UVB-exposed epidermal keratinocytes, ubiquinol10, RF and FMN predominantly interrupted the IL-1α and GM-CSF-stimulated expression of NEP in dermal fibroblasts. On the other hand, as for the UVA-associated mechanism, similar to the abrogating effects reported for AX and FMN, ubiquinol10 but not RF had the potential to abrogate the increased expression of NEP and matrix-metalloproteinase-1 in UVA-exposed human fibroblasts. Our findings strongly support the in vivo anti-wrinkling effects of ubiquinol10 and AX on human and animal skin and provide convincing proof of the UV-induced wrinkling mechanism that essentially focuses on the over-expression of NEP by dermal fibroblasts as an intrinsic causative factor.
Highlights
Ultraviolet irradiation serves as a harmful stimulus for human body and local homeostasis via the recently unveiled skin stress response mechanisms [1,2]
We recently characterized the epithelial-mesenchymal paracrine cytokine interactions between ultraviolet B (UVB)-exposed-keratinocytes and dermal fibroblasts in a co-culture system with cell culture inserts or by incubating the conditioned medium from UVB-exposed-keratinocytes with human fibroblasts. Both of those models identified the up-regulation of neutral endopeptidase (NEP) expression in human fibroblasts [13, 14, 15] and we found that interleukin-1α (IL-1α) and granulocyte macrophage colony stimulatory factor (GM-CSF) are intrinsic cytokines secreted by UVBexposed keratinocytes that stimulate the expression of NEP by fibroblasts [13, 14, 15]
On the other hand, when human dermal fibroblasts (HDFs) were directly exposed to UVB or UVA radiation, the expression of NEP at 72 h post-irradiation was significantly increased by UVA (10 J/cm2) at both the protein and enzymatic levels and by UVA (5 J/cm2) at the enzymatic level, but not by UVB (80 mJ/ cm2) at either the protein or enzymatic level and by UVA (5 J/cm2) at the protein level compared with the non-exposed control (Fig 1)
Summary
Ultraviolet irradiation serves as a harmful stimulus for human body and local homeostasis via the recently unveiled skin stress response mechanisms [1,2]. The three-dimensional alteration of elastic fibers has been substantiated by the marked and continuous up-regulation of an elastindegrading enzyme in wrinkled skin after repetitive UVB or UVA irradiation [9,10] as well as after ovariectomy [11] The sum of those studies strongly indicates that the up-regulated activity of skin fibroblast-derived elastase plays a pivotal role in the wrinkling of skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. We recently found that the direct UVA exposure of human fibroblasts elicits a significant increase in the expression of matrix metallo-protease (MMP)-1 as well as NEP at the transcriptional, translational and enzymatic levels [16, 17] This suggested that UVA-induced wrinkle formation is mediated at least via the up-regulated activity of NEP and/or MMP-1 derived from dermal fibroblasts. The sum of this evidence strongly indicates the possibility that substances with anti-wrinkling properties could preferentially have inhibitory effects on both the UVB-associated epithelial-mesenchymal cytokine interaction- and the UVA-induced up-regulation of NEP in fibroblasts
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