Abstract
Ceramide and sphingosine, generated by sphingomyelinase-mediated hydrolysis of sphingomyelin, which packs tightly in the bilayer of the plasma membrane, have been proposed as intracellular mediators of apoptotic signals. However, precise function of endogenous sphingomyelin-cycle metabolites in mast cells has been unclear. Thus, we sought to define the involvement of ceramide and sphingosine in apoptotic pathways of mast cells. We examined the effect of cell-permeable C(2)-ceramide, sphingosine, and sphingomyelinase on survival of murine bone marrow-derived cultured mast cells (BMCMC) supported by recombinant interleukin-3 (rIL-3) and/or recombinant stem cell factor (rSCF). Downstream signaling pathways of C(2)-ceramide and sphingosine were analyzed by using caspase inhibitors. C(2)-ceramide, sphingosine, and sphingomyelinase induced apoptosis in BMCMC in the presence of rIL-3 and/or rSCF, and Z-VAD-fmk (a broad caspase inhibitor), Z-DEVD-fmk (a caspase 3 inhibitor), and Z-IETD-fmk (a caspase 8 inhibitor) partially prevented apoptosis of BMCMC induced by C(2)-ceramide but not sphingosine. The present results suggest that ceramide and sphingosine may function as intracellular mediators of apoptotic signals in mast cells, which override survival signals from IL-3 and SCF. In addition, caspases may be partially involved in ceramide- but not sphingosine-mediated apoptosis of mast cells.
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