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

Biochem J. 1994 Oct 15;303 ( Pt 2)(Pt 2):341-5. doi: 10.1042/bj3030341.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • Cell Line
  • Enzyme Activation / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Humans
  • Hydrolysis / drug effects
  • Interleukin-1 / pharmacology*
  • Interleukin-1beta
  • Lysosomes / drug effects
  • Lysosomes / enzymology
  • Mitogens / pharmacology
  • Mucolipidoses / enzymology
  • Mucolipidoses / genetics
  • Mutation / genetics
  • Niemann-Pick Diseases / enzymology
  • Niemann-Pick Diseases / genetics
  • Peptide Fragments / pharmacology*
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Skin / cytology
  • Sphingomyelin Phosphodiesterase / deficiency
  • Sphingomyelin Phosphodiesterase / drug effects
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism*
  • Sphingomyelins / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Interleukin-1
  • Interleukin-1beta
  • Mitogens
  • Peptide Fragments
  • Recombinant Proteins
  • Sphingomyelins
  • Tumor Necrosis Factor-alpha
  • interleukin-1beta (163-171)
  • Sphingomyelin Phosphodiesterase