High level of phospholipase A(2) (PLA(2)) activity is found in serum and biological fluids during the acute-phase response (APR). Extracellular PLA(2) in fluids of patients with inflammatory diseases such as sepsis, acute pancreatitis or rheumatoid arthritis is also associated with propagation of inflammation. PLA(2) activity is involved in the release of both pro- and anti-inflammatory lipid mediators from phospholipids of cellular membranes or circulating lipoproteins. PLA(2) may thus generate signals that influence immune responses. Here, group III secretory PLA(2) were tested for their ability to promote generation of functionally mature human dendritic cells (DC). PLA(2) treatment of differentiating monocytes in the presence of granulocyte/macrophage colony-stimulating factor and IL-4 yielded cells with phenotypical and functional characteristics of mature DC. This maturation was dependent on the dose of PLA(2), and PLA(2)-generated DC stimulated IFN-gamma secretion by allogeneic T cells. The effects of PLA(2) on DC maturation was mainly dependent on enzyme activity and correlated with the activation of NF-kappaB, AP-1 and NFAT. The data suggest that transient increase in PLA(2) activity generates signals that promote transition of innate to adaptive immunity during the APR.