Ultraviolet A-induced signaling involves a ceramide-mediated autocrine loop leading to ceramide de novo synthesis.
Exposure of human keratinocytes to ultraviolet A (UVA) radiation at physiological doses leads to a biphasic activation of transcription factor activator protein-2 (AP-2) and subsequently to a biphasic increase in gene expression of, e.g. intercellular adhesion molecule-1 (ICAM-1). Both kinetics follow a pattern with a first peak between 0.5 and 2 h and a second, more sustained activation between 16 and 48 h. We have previously reported on a non-enzymatic triggering of the ceramide signaling cascade as the initiating step in UVA radiation-induced signaling. In this study, we report that this early (0.5-1 h) peak in ceramide content is followed by a second peak that (i) was associated with an increased expression and activity of serine palmitoyltransferase, the key enzyme of ceramide synthesis, (ii) could be prevented by inhibitors of this enzyme, and (iii) was of functional relevance because its inhibition abrogated the second, but not the first peak in UVA radiation-induced ICAM-1 gene expression. We hypothesize that this second peak most likely resulted from a ceramide-mediated autocrine loop, for (i) inhibition of the first ceramide peak resulted in inhibition of the second peak and (ii) cell-permeable ceramides-induced serine palmitoyltransferase expression, activity, and subsequently ceramide content.
Grether-Beck
Susanne
S
Institut fuer Umweltmedizinische Forschung at the Heinrich-Heine-University Duesseldorf gGmbH, Duesseldorf, Germany.
Timmer
Andreas
A
Felsner
Ingo
I
Brenden
Heidi
H
Brammertz
Daniela
D
Krutmann
Jean
J
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000599:Amino Acids, Diamino / Q000494:pharmacology; D019898:Autocrine Communication; D002518:Ceramides / Q000096:biosynthesis* / Q000494:pharmacology; D002784:Cholesterol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation; D014810:Vitamin E / Q000494:pharmacology
D000599:Amino Acids, Diamino; D002518:Ceramides; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C101954:N-caproylsphingosine; D018799:Intercellular Adhesion Molecule-1; D014810:Vitamin E; C045628:ectoine; D002784:Cholesterol; D000217:Acyltransferases; C495089:SPTLC2 protein, human; D051102:Serine C-Palmitoyltransferase