Lysophosphatidylcholine and arachidonic acid are required in the cytotoxicresponse of human natural killer cells to tumor target cells

Treatment of human natural killer (NK) cells with phospholipase A(2) (PLA(2 )) inhibitors, mepacrine and 4-bromophenacyl bromide (BPB), diminished thei r ability to lyse K562 target cells by as much as 100%. The ability of NK c ells to bind to K562 cells was significantly affected by BPB above 2 mu M, but not by mepacrine at any concentration tested. This indicates that BPB i s having effects on NK cells unrelated to its inhibition of PLA(2) activity at concentrations above 2 mu M. The activation of phospholipase C in respo nse to K562 cell binding (as measured by inositol phosphate turnover) was u naffected by inhibition of the PLA(2) activity. The products of PLA(2) cata bolism are a fatty acid (often arachidonic acid) and a lysophospholipid. In hibition of NK cytotoxicity by mepacrine or BPB is reversed significantly w hen lysophosphatidylcholine, but no other lysolipid, is added back to the N K cells before assaying for cytotoxicity. Arachidonic acid, but not linolei c acid, also significantly reverses inhibition of NK cytotoxicity, Finally, the 15-lipoxygenase product, 15S-hydroperoxyeicosatetraenoic acid (15S-HPE TE), is also able to reverse mepacrine-induced inhibition of NK cytotoxicit y, T fhe 5-lipoxygenase product 5S-HPETE was not effective. These data indi cate that PLA(2) activation is a necessary signal in human NK cytotoxicity and that it is not involved in protein tyrosine kinase and subsequent phosp holipase C activation; these latter two enzymes are also required in the cy totoxic response, Thus PLA(2) activation is either a more distal signal, de pendent on activation of some earlier signal, or an independent cosignal st imulated by tumor-target binding which generates lysophosphatidylcholine, a rachidonic acid, and/or a lipoxygenase product(s). Copyright (C) 1999 S. Ka rger AG,Basel.