Discrete roles of intracellular phospholipases A2 in human neutrophil cytotoxicity :

An in vitro technique is described for assessing the chemotactic activity of soluble substances on motile cells. Antibody-antigen mixtures when incubated (37°C) in medium containing fresh (i.e. non-inactivated) normal rabbit serum exert a strong chemotactic effect on rabbit polymorphonuclear leucocytes. Results are described which indicate that, when antibody-antigen complexes are incubated (37°C) in fresh serum, a heat-stable (56°C) substance (or substances) is produced which acts directly as a chemotactic stimulus on the polymorphs. This heat-stable chemotactic substance is not produced when antibody-antigen complexes are incubated in serum which has been heated at 56°C for 30 minutes.

Mammalian genomes encode genes for more than 30 phospholipase A₂s (PLA₂s) or related enzymes, which are subdivided into several classes including low-molecular-weight secreted PLA₂s (sPLA₂s), Ca²+-dependent cytosolic PLA₂s (cPLA₂s), Ca²+-independent PLA₂s (iPLA₂s), platelet-activating factor acetylhydrolases (PAF-AHs), lysosomal PLA₂s, and a recently identified adipose-specific PLA. Of these, the intracellular cPLA₂ and iPLA₂ families and the extracellular sPLA₂ family are recognized as the "big three". From a general viewpoint, cPLA₂α (the prototypic cPLA₂ plays a major role in the initiation of arachidonic acid metabolism, the iPLA₂ family contributes to membrane homeostasis and energy metabolism, and the sPLA₂ family affects various biological events by modulating the extracellular phospholipid milieus. The cPLA₂ family evolved along with eicosanoid receptors when vertebrates first appeared, whereas the diverse branching of the iPLA₂ and sPLA₂ families during earlier eukaryote development suggests that they play fundamental roles in life-related processes. During the past decade, data concerning the unexplored roles of various PLA₂ enzymes in pathophysiology have emerged on the basis of studies using knockout and transgenic mice, the use of specific inhibitors, and information obtained from analysis of human diseases caused by mutations in PLA₂ genes. This review focuses on current understanding of the emerging biological functions of PLA₂s and related enzymes. Copyright © 2010 Elsevier Ltd. All rights reserved.

1. Neutrophil priming by agents such as tumour necrosis factor-alpha, granulocyte/macrophage colony-stimulating factor and lipopolysaccharide causes a dramatic increase in the response of these cells to an activating agent; this process has been shown to be critical for neutrophil-mediated tissue injury both in vitro and in vivo. 2. The principle consequence of priming, aside from a direct effect on cell polarization, deformability and integrin/selectin expression, is to permit secretagogue-induced superoxide anion generation, degranulation and lipid mediator (e.g. leukotriene B4 and arachidonic acid) release. It is now recognized that most priming agents also serve an additional function of delaying apoptosis and hence increasing the functional longevity of these cells at the inflamed site. 3. The potential mechanisms underlying priming are discussed; current data suggest a dissociation between priming and changes in receptor number and/or affinity, G-protein expression, phospholipase C and phospholipase A2 activation and changes in intracellular Ca2+ concentration. However, more recent studies support a key role for protein tyrosine phosphorylation and enhanced phospholipase D and phosphoinositide 3-kinase activity in neutrophil priming. 4. Recent work has also revealed the potential for neutrophils to spontaneously and fully 'de-prime' after an initial challenge with platelet-activating factor. This ability of neutrophils to undergo a complete cycle of priming-de-priming (and re-priming) reveals a previously unrecognized flexibility in the control of neutrophil behaviour at an inflamed site.