Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha.

摘要: A sphingomyelin (SM)-signaling cycle has been described in human leukemia-derived HL-60 cells (Okazaki, T., Bell, R.M., and Hannun, Y.A. (1989) J. Biol. Chem. 264, 19076-19080). Activation of the by tumor necrosis factor alpha (TNF alpha) occurs rapidly, with peak levels approximately 30% SM hydrolysis observed within 45-60 min. The mechanisms which TNF induces this turnover remain largely unexplored. In study, arachidonic acid (AA) was investigated as a potential mediator effects on turnover. cells, 30 nM stimulated release AA 5-10 turn, concomitant ceramide generation 20 min addition to cells. Other fatty acids, notably oleate, mimicked hydrolysis, but methyl ester alcohol analogs acids were inactive. Diacylglycerol, candidate responses, activated cytosolic sphingomyelinase dose dependently, 10-100 microM including 3-4-fold activation, thus suggesting direct effect sphingomyelinase. Melittin, potent phospholipase A2 activator, induced at concentrations low 35 nM. However, unlike AA, melittin unable stimulate activation an vitro assay system. Finally, exogenous also produced antiproliferative reminiscent effects. Thus, role for A2/AA pathway mediating induction is supported multiple lines evidence. These studies begin elucidate mechanism signaling identify close relationship between glycerophospholipid sphingolipid signaling. therefore, may be pivotal understanding sphingomyelin-signaling cascade.