Role of cytosolic phospholipase A(2) in the production of lipid mediators and histamine release in mouse bone-marrow-derived mast cells

Cytosolic phospholipase A(2) (cPLA(2)) plays a critical role in mast-cell-r elated allergic responses [Uozumi, Kume, Nagase, Nakatani, Ishii, Tashiro, Komagata, Maki, Ikuta, Ouchi et al. (1997) Nature (London) 390, 618-622]. B one-marrow-derived mast cells from mice lacking cPLA(2) (cPLA(2)(-/-) mice) were used in order to better define the role of cPLA(2) in the maturation and degranulation of such cells. Cross-linking of high-affinity receptors f or IgE (Fc epsilon RI) on cells from cPLA(2)(-/-) mice led to the release o f negligible amounts of arachidonic acid or its metabolites, the cysteinyl leukotrienes and prostaglandin D-2, indicating an essential role for cPLA(2 ) 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(2)(-/-) mice, the ratios of release of histamine and beta -hexosaminidase were, paradoxically, significantly h igher for cells from cPLA(2)(-/-) 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(2)(-/-) mice than in those from wild-type mic e. Thus the loss of cPLA(2) not only diminishes the release of lipid mediat ors, but also alters degranulation. While the overall effect is still a dec rease in the release of mast cell mediators, explaining the in vivo finding s, the present study proposes a novel link between cPLA(2) and the degranul ation machinery.