Abstract
Abstract: :
Purpose: The results of epidemiological investigation have indicated that ultraviolet irradiation (UV) not only causes human skin damage, leading to skin aging and skin cancer, but also coincides with cataractogenesis. While the molecular mechanisms of UV–induced skin damage have been well established, the cellular signaling of UV–induced cataract remains virtually terra incognita. Our previous studies indicate that UV irradiation induces human skin damage through activation of MAP kinases and overexpression of matrix metalloproteinases that break down the collagen in human skin. With the knowledge attained from human skin studies, we examined the signaling pathways that may lead to the formation of cataract. Methods: Human lens cells were cultured and irradiated with UVB/A2. Biochemical analysis was performed. Results: We found that UV irradiation induced p38 and JNK kinase activation in a dose and time dependent manner in cultured human lens cells. Phosphorylation of p38 started at 15 min post UV irradiation, peaked about 30min and remained elevated for up to 4 hrs. Similarly, JNK phosphorylation started 30min post UV, peaked about 4 hrs and remained elevated for 8 hrs. We also found that hydrogen peroxide induced p38 and JNK activation. DPI, an inhibitor of NADPH oxidase, inhibited UV–induced p38 and JNK activation. Interestingly, UV transiently induced IΚB degradation in 5 min and IΚB level returned to the basal within 15 min. NFΚB translocation from cytoplasm to nucleus was barely observable. Western blot analysis showed that UV induced phosphorylation of AKT in a time dependent manner. AKT phosphorylation started at 15 min post UV, peaked at about 30min and remained elevated for up to 2 hrs. Treatment of human lens cells with UV and sorbitol or NaCl synergistically induced p38 and JNK phosphorylation. Citrus flavonoids inhibited UV–induced p38 and JNK phosphorylation in human lens cells. Conclusions: Collectively, we conclude that UV induces MAP kinase activation via redox–sensitive pathway and antioxidants such as citrus flavonoids may be used to attenuate UV–induced human lens cell damage.
Keywords: antioxidants • signal transduction • cataract