TGF-β1调控PPARγ表达在UVB诱导的衰老成纤维细胞中作用

Repeated exposure of ultraviolet (UV) resulted in acceleration of skin aging. The dermal fibroblasts, which suffer accumulated damage during UV irradiation, are gaining attention in the aging process due to their important role in maintaining the metabolic balance of dermal extracellular matrix. It is reported that the activation of TGF-β1 signal transduction pathway caused by UVB leads to aging phenotype. However, the downstream responding factor remains to be investigated. Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor family, has been recently reported to be involved in the anti-aging effect in a aging model induced by UVB. Also, we found that PPARγ was down-regulated by UVB in a dose-dependent manner and had a negative correlation with the expression of TGF-β1. We suggest that the UVB regulates aging phenotype by UVB-TGF-β1-PPARγ axis. The relationship of TGF-β1 signal transduction pathway and PPARγ will be illustrated by UVB-induced aging model. Moreover, the anti-aging effect by activation of PPARγ will provide a new target for the further treatment of photoaging.

日光中的中波紫外线（UVB）是加速皮肤衰老的关键因素。成纤维细胞（FB）作为真皮主体细胞成分，在衰老进程中的作用越来越得到重视。UVB可通过激活TGF-β1信号通路引起FB出现一系列衰老表型，但该通路下游作用因子尚不明确。细胞核内过氧化物酶体增殖物激活受体-gamma（PPARγ）被证实具有潜在抗衰老能力，在UVB作用下呈下调趋势，前期研究证实TGF-β1和PPARγ存在负相关关系，由此我们提出UVB-TGF-β1-PPARγ调控轴的概念，即UVB通过激活TGF-β1抑制核内PPARγ的转录和功能。通过在体外构建UVB诱导的衰老模型，可明确TGF-β1信号通路与PPARγ的相互关系，以阐明UVB引起FB衰老的分子机制；同时验证PPARγ抗衰老的作用，为临床治疗光老化提供新的位点。

日光中的中波紫外线（UVB）是加速皮肤衰老的关键因素。成纤维细胞（FB）作为真皮主体细胞成分，在衰老进程中的作用越来越得到重视。UVB可通过激活TGF-β1信号通路引起FB出现一系列衰老表型，但该通路下游作用因子尚不明确。本项目首先通过采用亚细胞毒剂量UVB反复照射小鼠皮肤成纤维细胞（MDFs），成功地建立了稳定的、可重复的体外光老化模型。在此基础上研究发现SIPS模型中TGF-β1通路和细胞核内过氧化物酶体增殖物激活受体-gamma（PPARγ）之间存在相互拮抗的关系，这提示了UVB—TGF-β1—PPARγ调控轴存在的可能。通过沉默TGF-β1达到了一定程度的缓解光老化衰老表型的效果。并通过进一步实验阐明PPAR-γ发挥光老化保护作用的可能机制：在分子水平上通过增加CAT的表达来增加细胞的总抗氧化性，进而提高了细胞的光老化抗性，这也为光老化的治疗提供了一个新的思路。此外，目前正在进行的光老化MDFs中TGF-β1主要改变通路及相关基因的筛选对进一步阐述光老化的机制及治疗均具有重要意义。