Sphingosine 1-phosphate protects primary human keratinocytes from apoptosis via nitric oxide formation through the receptor subtype S1P3

• Published in: Molecular and cellular biochemistry 2012-12, Vol.371 (1-2), p.165-176
• Main Authors: Schmitz, Elisabeth I., Potteck, Henrik, Schüppel, Melanie, Manggau, Marianti, Wahydin, Elly, Kleuser, Burkhard
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Cardiology; Life Sciences; Medical Biochemistry; Oncology
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-012-1433-5

Although the lipid mediator sphingosine 1-phosphate (S1P) has been identified to induce cell growth arrest of human keratinocytes, the sphingolipid effectively protects these epidermal cells from apoptosis. The molecular mechanism of the anti-apoptotic action induced by S1P is less characterized. Apart from S1P, endogenously produced nitric oxide (NO • ) has been recognized as a potent modulator of apoptosis in keratinocytes. Therefore, it was of great interest to elucidate whether S1P protects human keratinocytes via a NO • -dependent signalling pathway. Indeed, S1P induced an activation of endothelial nitric oxide synthase (eNOS) in human keratinocytes leading to an enhanced formation of NO • . Most interestingly, the cell protective effect of S1P was almost completely abolished in the presence of the eNOS inhibitor L-NAME as well as in eNOS-deficient keratinocytes indicating that the sphingolipid metabolite S1P protects human keratinocytes from apoptosis via eNOS activation and subsequent production of protective amounts of NO • . It is well established that most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Therefore, the involvement of S1P-receptor subtypes in S1P-mediated eNOS activation has been examined. Indeed, this study clearly shows that the S1P 3 is the exclusive receptor subtype in human keratinocytes which mediates eNOS activation and NO • formation in response to S1P. In congruence, when the S1P 3 receptor subtype is abrogated, S1P almost completely lost its ability to protect human keratinocytes from apoptosis.