Involvement of PI3Kγ in Superoxide Anion Production in Response to IL-8, RANTES, and fMLP in Human Peripheral Blood Neutrophils

Abstract

Involvement of PI3Kγ in Superoxide Anion Production in Response to IL-8, RANTES, and fMLP in Human Peripheral Blood Neutrophils Neutrophils are essential components of the immune system and have a critical role in combating bacterial and fungal infections. A key weapon in the neutrophil armory is the “respiratory burst,” which is the generation of reactive oxygen species (ROS) by a multicomponent oxidase complex. It is well established that pre-exposure of human neutrophils to proinflammatory cytokines and chemokines markedly augments the production of reactive oxygen species (ROS) to subsequent stimuli. In inflammatory reactions there are complex interactions of protein mediators (cytokines) and mediators derived from lipids. An important event in inflammation is superoxide production, in relation to microbicidal activity as well as tissue damage. A better understanding of phenomena involved in the regulation of NADPH oxidase could help developing novel therapeutic agents for inflammatory diseases involving abnormal neutrophil superoxide. Therefore, stimulating superoxide production by human neutrophils was investigated for this reason and because it sheds a light on intracellular signals that activate this response. Pretreatment of human neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL-8), and regulated on activation, normal T cell expressed and secreted (RANTES) markedly augmented the amount of superoxide anion produced, which was inhibited completely (IL-8 and fMLP) or partially (RANTES) by a specific isoform of phosphoinositide 3-kinase (PI3K), the PI3KγII inhibitor.