Non-enzymatic triggering of the ceramide signalling cascade by solar UVA radiation

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Abstract
Ceramide is a key component of intracellular stress responses. Evidence is provided for a novel mechanism of ceramide formation that mediates solar ultraviolet (UV) A radiation‐induced expression of the intercellular adhesion molecule (ICAM)‐1. Similarly to UVA radiation, ceramide stimulation of human keratinocytes induced ICAM‐1 mRNA expression and activated the ICAM‐1 promoter through transcription factor AP‐2. Ceramide‐activated AP‐2 and ceramide‐induced ICAM‐1 reporter gene activation were abrogated through deletion of the AP‐2 binding site. UVA radiation increased the level of ceramide in keratinocytes and inhibition of sphingomyelin synthesis prevented UVA radiation‐induced ICAM‐1 expression. Hitherto, two pathways have been identified for ceramide accumulation: hydrolysis from sphingomyelin through neutral and acid sphingomyelinases, and de novo synthesis by ceramide synthase. UVA radiation did not activate any of these enzymes. Ceramide generation in UVA‐irradiated cells, however, was inhibited by singlet oxygen quenchers and mimicked in unirradiated cells by a singlet oxygen‐generating system. In addition, UVA radiation and singlet oxygen both generated ceramide in protein‐free, sphingomyelin‐containing liposomes. This study indicates that singlet oxygen triggers a third, non‐enzymatic mechanism of ceramide formation.