INVOLVEMENT OF PHOSPHOLIPASE-A2 ACTIVATION IN TUMOR-CELL KILLING BY TUMOR NECROSIS FACTOR

  • 1 May 1988
    • journal article
    • research article
    • Vol. 64  (1) , 81-85
Abstract
Earlier studies have indicated a possible role for arachidonate metabolism in the direct cytolysis of tumor cells by tumor necrosis factor (TNF) in vitro. In this study, the involvement of arachidonate metabolism has been investigated further with the following results: (i) Cytolysis of human U937 tumor cells by recombinant TNF was reduced by dexamethasone and quinacrine, agents which inhibit phospholipase A2. (ii) U937 and L929 cells, which are susceptible to TNF cytolysis, released arachidonic acid and its metabolites within 5 hr of TNF challenge, before cell death was apparent. In contrast, U937/R and L929/R, which are resistant to the cytolytic effects of TNF, did not release arachidonate products on TNF challenge. (iii) rTNF cytolysis of U937 cells was not reduced by inhibitors of the cyclo-oxygenase and lipo-oxygenase pathways of arachidonic acid metabolism. Cytolysis was reduced, however, by inhibitors of the arachidonate metabolic pathway involving cytochrome P450-dependent reductase, but only at reagent concentrations that also inhibited phospholipase A2 activity. Overall, these observations indicate a role for phospholipase A2 but not for arachidonic acid or its metabolites in the direct cytolysis of tumor cell lines by TNF.