Calcium-independent phospholipase A2 and apoptosis.

Apoptosis or programmed cell death is associated with changes in glycerophospholipid metabolism. Cells undergoing apoptosis generally release free fatty acids including arachidonic acid, which parallels the reduction in cell viability. The involvement of cytosolic group IVA phospholipase A(2)alpha (cPLA(2)alpha) in apoptosis has been the subject of numerous studies but a clear picture of the role(s) played by this enzyme is yet to emerge.

Oxidative stress and arachidonic acid mobilization.

Reactive oxygen species are known to contribute to tissue damage during injury and inflammation. However, these species can also be sensed by the cells and trigger intracellular signaling cascades. This review examines recent evidence on the involvement of reactive oxygen species in lipid signaling.

Involvement of group VIA calcium-independent phospholipase A2 in macrophage engulfment of hydrogen peroxide-treated U937 cells.

Hydrogen peroxide-induced apoptosis of U937 cells results in substantial hydrolysis of membrane phospholipids by calcium-independent group VIA phospholipase A(2) (iPLA(2)-VIA). However, abrogation of cellular iPLA(2)-VIA neither delays nor decreases apoptosis, suggesting that, beyond a mere destructive role, iPLA(2)-VIA may serve other specific roles. In this study, we report that phagocytosis of apoptosing U937 cells by macrophages is blunted if the cells are depleted of iPLA(2)-VIA by treatment with an inhibitor or an antisense oligonucleotide, and it is augmented by overexpression of iPLA(2)-VIA in the dying cells.

Overexpression of cytosolic group IVA phospholipase A2 protects cells from Ca2+-dependent death.

The calcium ionophore ionomycin induces apoptosis-like events in the human embryonic kidney cell line at early times. Plasma membrane blebbing, mitochondrial depolarization, externalization of phosphatidylserine, and nuclear permeability changes can all be observed within 15 min of treatment. However, there is no activation of caspases or chromatin condensation.

Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells.

Arachidonic acid (AA) participates in a reacylation/deacylation cycle of membrane phospholipids, the so-called Lands cycle, that serves to keep the concentration of this free fatty acid in cells at a very low level. To manipulate the intracellular AA level in U937 phagocytes, we have used several pharmacological strategies to interfere with the Lands cycle. We used inhibitors of the AA reacylation pathway, namely thimerosal and triacsin C, which block the conversion of AA into arachidonoyl-CoA, and a CoA-independent transacylase inhibitor that blocks the movement of AA within phospholipids.