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Pathway-Specific Effect of Caffeine on Protection against UV Irradiation–Induced Apoptosis in Corneal Epithelial Cells

From the Department of Medicine, HMC, David Geffen School of Medicine, University of California Los Angeles, Torrance, California.

PURPOSE. To define the role of molecular interaction between the UV-induced JNK (c-Jun N-terminal kinase) cascade and corneal epithelial cell apoptosis and protection against apoptosis by caffeine.

METHODS. Rabbit and human corneal epithelial cells were cultured in DMEM/F12 medium containing 10% FBS and 5 µg/mL insulin at 37°C in 5% CO₂. DNA fragmentation and ethidium bromide/acridine orange (EB/AO) nuclear staining were performed to detect cell death. Western blot, immunoprecipitation, and kinase assays were used to measure UV-induced mitogen-activated protein (MAP) kinase activity.

RESULTS. UV irradiation–induced apoptosis through apoptosis signal-regulating kinase 1 (ASK1) and MAKK4 (SEK1) upstream from JNK was caffeine sensitive. Caffeine (1,3,7-trimethylxanthine), an agent that is one of the most popular additions to food consumed in the world and a potential enhancer of chemotherapy, effectively protected corneal epithelial cells against apoptosis by its specific effect on the JNK cascade. Theophylline (1,3-dimethylxanthine) exhibited an effect similar to that of caffeine on prevention of UV irradiation–induced apoptosis. However, alterations of either intracellular cAMP or Ca²⁺ levels did not alter the effect of caffeine on the JNK signaling pathway. In addition, the blockade of PI3K-like kinases by wortmannin had no impact on the protective effect of caffeine against UV irradiation–induced apoptosis, suggesting that the protective effect of caffeine acts through a specific mechanism involving UV irradiation–induced activation of ASK1 and SEK1. In contrast, caffeine had no effects on melphalan-, hyperosmotic stress–, or IL-1ß-induced activation of the JNK signaling pathway in these cells.

CONCLUSIONS. UV irradiation stress–induced activation of the ASK1-SEK1-JNK signaling pathway leading to apoptosis is a caffeine-sensitive process, and caffeine, as a multifunctional agent in cells, can specifically interact with the pathway to protect against apoptosis.

This article has been cited by other articles:

				L. Wang, W. Dai, and L. Lu Stress-induced c-Jun Activation Mediated by Polo-like Kinase 3 in Corneal Epithelial Cells J. Biol. Chem., November 2, 2007; 282(44): 32121 - 32127. [Abstract] [Full Text] [PDF]