Modulation of ceramide-induced NF-kappaB binding activity and apoptotic response by caffeic acid in U937 cells: comparison with other antioxidants

Ceramide acts as second messenger in the signal transduction triggered by a variety of stress stimuli and extracellular agents. Stress response through ceramide is involved in the development of many human diseases, such as atherosclerosis, inflammation, neurodegenerative disorders, and acquired immunodeficiency syndrome. Dietary polyphenols have been reported to exert a beneficial effect on the onset and development of most of these human chronic-degenerative pathologies. However, the mechanisms underlying this beneficial effect are mostly not understood at the present. To investigate the ability of polyphenols in modulating fundamental cellular functions, we studied the effect of caffeic acid, a widespread phenolic acid largely present in human diet, in the modulation of ceramide-induced signal transduction pathway leading to apoptosis in U937 cells, in comparison with other established antioxidants of nutritional interest (N-acetylcysteine, d-alpha-tocopherol acetate and ascorbic acid). Our results indicate that caffeic acid efficiently inhibits both ceramide-induced NF-kappaB binding activity and apoptosis at micromolar concentration. Other antioxidants tested are totally ineffective in inhibiting apoptosis, although affecting NF-kappaB activation. Caffeic acid was found to inhibit protein tyrosine kinase activity, suggesting that this mechanism can be on the basis of the inhibition of apoptosis. Our results suggest that dietary caffeic acid might modulate ceramide-induced signal transduction pathway and NF-kappaB activation through either antioxidant and nonantioxidant mechanisms.