Phosphorylation of the Immunomodulator FTY720 Inhibits Programmed Cell Death of Fibroblasts Via the S1P3 Receptor Subtype and Bcl-2 Activation

Cellular Physiology and Biochemistry

关键词: FTY720;    S1P3;    Fibroblasts;    Bcl-2;    Mitochondria;   

DOI  :  10.1159/000315107

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inhibiting lymphocyte egress from secondary lymphoid tissues. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate (FTY720-P), which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. Despite its homology to S1P, which exerts antiapoptotic actions in different cells, FTY720 has also been reported to be able to induce apoptosis in a variety of cells. Methods Therefore, we investigated the action of both, FTY720 and its phosphorylated version FTY720-P, on apoptosis. Moreover, signalling pathways of apoptosis in response to FTY720 and FTY720-P were examined. Results and Conclusions Although FTY720 acts apoptotic at micromolar concentrations in human fibroblasts the phosphorylated compound FTY720-P possesses a pronounced antiapoptotic effect counteracting FTY720-induced programmed cell death. Interestingly, none of the classical antiapoptotic pathways like MAP kinases, Akt or mTOR play a role in the protective role of FTY720-P. Most important, we identified that the S1P₃ receptor subtype is involved in the antiapoptotic action of FTY720-P leading to an increased phosphorylation of Bcl-2 and changes in the mitochondrial membrane potential.

【 授权许可】

CC BY-NC-ND