Role of cytosolic phospholipase A2 in the production of lipid mediators and histamine release in mouse bone-marrow-derived mast cells

Abstract

Cytosolic phospholipase A2 (cPLA2) plays a critical role in mast-cell-related allergic responses [Uozumi, Kume, Nagase, Nakatani, Ishii, Tashiro, Komagata, Maki, Ikuta, Ouchi et al. (1997) Nature (London) 390, 618–622]. Bone-marrow-derived mast cells from mice lacking cPLA2 (cPLA-/- mice) were used in order to better define the role of cPLA2 in the maturation and degranulation of such cells. Cross-linking of high-affinity receptors for IgE (FcεRI) on cells from cPLA-/-mice led to the release of negligible amounts of arachidonic acid or its metabolites, the cysteinyl leukotrienes and prostaglandin D2, indicating an essential role for cPLA2 in the production of these allergic and pro-inflammatory lipid mediators. In addition, the histamine content of the mast cells and its release from the cells were reduced to 60%. While these results are in agreement with a reduced anaphylactic phenotype of cPLA-/- mice, the ratios of release of histamine and β-hexosaminidase were, paradoxically, significantly higher for cells from cPLA-/- mice than for those from wild-type mice. Consistently, IgE-induced calcium influx in mast cells was greater and more prolonged in cells from cPLA-/- mice than in those from wild-type mice. Thus the loss of cPLA2 not only diminishes the release of lipid mediators, but also alters degranulation. While the overall effect is still a decrease in the release of mast cell mediators, explaining the in vivo findings, the present study proposes a novel link between cPLA2 and the degranulation machinery.