Evidence against involvement of the acid lysosomal sphingomyelinase in the tumor-necrosis-factor- and interleukin-1-induced sphingomyelin cycle and cell proliferation in human fibroblasts.
The hydrolysis of sphingomyelin (SPM) has been reported to mediate a number of responses to extracellular agents, including cytokines. The so-called SPM cycle may result from the activation of different types of sphingomyelinases (SPMases). We investigated the hypothetical contribution of acid lysosomal SPMase in the SPM signal-transduction pathway. We examined the ability of human skin fibroblasts with a genetic deficiency of acid lysosomal SPMase activity to respond to tumour necrosis factor alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta). We report that both cytokines promoted SPM hydrolysis in fibroblasts derived from patients with Niemann-Pick disease or I-cell disease, similar to that observed in normal cells. Treatment of normal fibroblasts with cationic 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 [3H]thymidine incorporation in Niemann-Pick fibroblasts, as in normal cells. Thus our results argue against a role for acid endolysosomal SPMase in mediating the cytokine-induced SPM signalling cascade.
CJF INSERM 9206, Institut Louis Bugnard, C.H.U. Rangueil, Toulouse, France.
N
N
Andrieu
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R
Salvayre
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T
Levade
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D053583:Interleukin-1beta; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008934:Mitogens / Q000494:pharmacology; D009081:Mucolipidoses / Q000201:enzymology / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009542:Niemann-Pick Diseases / Q000201:enzymology / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000166:cytology; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D053583:Interleukin-1beta; D008934:Mitogens; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171); D013108:Sphingomyelin Phosphodiesterase