EVIDENCE AGAINST INVOLVEMENT OF THE ACID LYSOSOMAL SPHINGOMYELINASE IN THE TUMOR-NECROSIS-FACTOR-INDUCED AND INTERLEUKIN-1-INDUCED SPHINGOMYELIN CYCLE AND CELL-PROLIFERATION IN HUMAN FIBROBLASTS

The hydrolysis of sphingomyelin (SPM) has been reported to mediate a n umber of responses to extracellular agents, including cytokines. The s o-called SPM cycle may result from the activation of different types o f sphingomyelinases (SPMases). We investigated the hypothetical contri bution of acid lysosomal SPMase in the SPM signal-transduction pathway . We examined the ability of human skin fibroblasts with a genetic def iciency of acid lysosomal SPMase activity to respond to tumour necrosi s factor alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta). We repor t that both cytokines promoted SPM hydrolysis in fibroblasts derived f rom patients with Niemann-Pick disease or I-cell disease, similar to t hat observed in normal cells. Treatment of normal fibroblasts with cat ionic amphiphilic drugs resulted in inhibition of acid SPMase activity , but had no effect on cytokine-induced SPM turnover. In addition, TNF -alpha and IL-1 beta stimulated [H-3]thymidine incorporation in Nieman n-Pick fibroblasts, as in normal cells. Thus our results argue against a role for acid endolysosomal SPMase in mediating the cytokine-induce d SPM signalling cascade.