Involvement of TGF-beta in Skin Photoaging

The goal of this thesis study was to understand the role of TGF-3 in skin photoaging, especially in solar elastosis. Solar elastosis, the accumulation of elastotic material in the dermal extracellluar matrix, is a major hallmark of photoaging. However, the mechanisms by which UV radiation causes solar elastosis are poorly understood. TGF-3 is a multifunctional cytokine involved in the regulation of extracelluar matrix and is known to be up-regulated by UVR. Involvement of reactive oxygen species (ROS) in the development of solar elastosis has been demonstrated by many studies using antioxidants and anti-inflammatory agents in the mouse skin in vivo. We hypothesized that ROS produced by TGF-P3 are key components in the tropoelastin (TE, a soluble precursor of elastin) up-regulation in dermal fibroblasts, and that TGF-P3 is a major regulator in the photoaging processes. Using human skin fibroblasts system in vitro, we found that ROS generated from NADPH oxidase and mitochondria are involved in the TGF-3 induced elastin production, and intracellular sources of ROS vary with time. We showed that both Smad and non-Smad pathways, e.g. MAPK and PKC pathways, are required for TE mRNA up-regulation by TGF-3. However, ROS were not involved in some of the important steps in these pathways, such as phosphorylations of p38 or ERK or Smad2, suggesting that ROS acts downstream of these pathways. The in vivo chronic UVB irradiation study using a Skh1 hairless mouse model with a small molecule inhibitor for the TGF,3 type I receptor showed that the TGF-P receptor inhibitor increased the number of mast cells, but decreased the levels of active TGF-[3 protein, and mRNA levels for collagen III and IV, MMP-2 and 9, and TE in the chronically UVB irradiated mouse skin. However, those responses did not result in the changes in the collagen and elastin content, or the wrinkle formation. Overall, this work indicates that TGF-3 contributes to the solar elastosis, through the effects on the TE mRNA level in skin. Implication of this