DISTINCTIVE INHIBITORY ACTIVITY OF DOCOSAHEXAENOIC ACID AGAINST SPHINGOSINE-INDUCED APOPTOSIS

The effect of supplementation of docosahexaenoic acid (DHA) on the apo ptosis of HL60 cells was examined using N-acetyl sphingosine (C-2-cera mide) and sphingosine as apoptosis-inducing agents. Although C-2-ceram ide-induced apoptosis was not affected by DHA supplementation, sphingo sine-induced apoptosis was reduced almost to the background level by p reincubation with 10 mu M DHA for 24 h. Among the fatty acids, only DH A appeared to be endowed with the ability to reduce sphingosine-induce d apoptosis, whereas, other unsaturated fatty acids, such as arachidon ic acid (AA) and eicosapentaenoic acid (EPA), did not show this activi ty. Incubation of HL60 with DHA within 6 h did not affect the apoptosi s, suggesting that DHA probably expressed the inhibitory activity afte r modulation of the membrane fatty acid composition. DHA also attenuat ed the apoptosis induced by dimethylsphingosine and H-7, but not by ca lphostin C, indicating that enrichment of DHA in membranous phospholip id does not necessarily prevent all of the apoptosis associated with t he inhibition of protein kinase C. The mechanism of the inhibition aga inst sphingosine-induced apoptosis by DHA remains to be further explor ed. However, the inhibition of cytosolic phospholipase A(2)(cPLA(2)) m ay be involved in the mechanism, because distinctive inhibitory activi ty of DHA against cPLA(2) has been demonstrated [M. Shikano, Y. Masuza wa, K. Yazawa, K. Takayama, I. Kudo, K. Inoue, Biochim, Biophys. Acta, 1212, 1994, 211-216], and arachidonyl trifluoromethylketone,a specifi c inhibitor of cPLA(2), attenuated the apoptosis induced by sphingosin e. (C) 1998 Elsevier Science B.V.