Imokawa Genji, Nakajima Hiroaki, Ishida Koichi
Research Institute for Biological Functions, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan.
School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo 192-0982, Japan.
Int J Mol Sci. 2015 Apr 8;16(4):7776-95. doi: 10.3390/ijms16047776.
Our previous studies strongly indicated that the up-regulated 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 fibroblast-derived elastase as a previously known enzyme, neprilysin or neutral endopeptidase (NEP). We have also 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 metallo-protease(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 UVA-exposed 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.
我们之前的研究强烈表明，皮肤成纤维细胞源性弹性蛋白酶活性上调通过损害弹性纤维结构及随后皮肤弹性丧失，在皮肤皱纹和/或松弛中起关键作用。幸运的是，我们成功鉴定出人类皮肤成纤维细胞源性弹性蛋白酶为一种已知的酶，即中性内肽酶或中性肽链内切酶（NEP）。我们还对紫外线B照射的角质形成细胞与真皮成纤维细胞之间的上皮-间充质旁分泌细胞因子相互作用进行了表征，发现白细胞介素-1α和粒细胞巨噬细胞集落刺激因子（GM-CSF）是紫外线B照射的角质形成细胞分泌的内在细胞因子，可刺激成纤维细胞表达中性内肽酶。另一方面，人类成纤维细胞直接暴露于UVA可显著刺激IL-6的分泌，还可引起基质金属蛋白酶（MMP）-1以及中性内肽酶（程度较轻）基因表达的显著增加，随后其蛋白质和酶活性水平明显升高。人类角质形成细胞直接暴露于UVA也会刺激IL-6、IL-8和GM-CSF的分泌，但不会刺激IL-1和内皮素-1的分泌。这些发现表明，紫外线A照射的角质形成细胞分泌的GM-CSF以及紫外线A照射的真皮成纤维细胞分泌的IL-6，分别通过上调真皮成纤维细胞中的中性内肽酶和MMP-1，在紫外线A诱导的皮肤松弛和皱纹形成中发挥重要的额外作用。
