Tumor necrosis factor α (TNFα) stimulated rapid (seconds) hydrolysis of sphingomyelin in HL-60 cells, formation of phosphocholine (PCho) and a decrease in choline. The response to TNFα was concentration dependent with a maximal effect at 3-10 nM. The monoclonal antibody (mAb). htr-9, which behaves as an agonist at the 55 kDa subtype of the TNF receptor, also stimulated sphingomyelin hydrolysis in intact cells. In contrast, the mAb, utr-1, which behaves as an antagonist at the 75 kDa receptor subtype, had no effect on sphingomyelin hydrolysis either on its own or in the presence of TNFα. In addition, htr-9 or TNFα stimulated hydrolysis of sphingomyelin in a membrane fraction of HL-60 cells. These results are consistent with a role of sphinpomyelin hydrolysis as an early event in the signalling mechanism or TNFα, and suggest that this pathway is activated through the 55 kDa subtype of the TNF receptor.
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