FMet-Leu-Phe stimulates proinflammatory cytokine gene expression in human peripheral blood monocytes: The role of phosphatidylinositol 3-kinase

The fMLP-stimulated release of proinflammatory cytokines such as IL-1 by hu man peripheral blood monocytes is an important component of the inflammator y process. The signaling mechanisms used by fMLP to stimulate the release o f cytokines are still incompletely understood. We previously demonstrated t hat fMLP-stimulated NF-kappa B activation in PBMC and now we present eviden ce that the lipid products of phosphatidylinositol 3-kinase (PI 3-kinase) a re required for fMLP-stimulated activation of NF-kappa B. Pretreatment with the PI 3-kinase inhibitors, wortmannin and LY294002, effectively blocked f MLP-induced IL-1 beta gene expression as well as NF-kappa B activation, Tra nsient transfection of THP1 cells with a dominant-negative mutant of the PI 3-kinase p85 subunit also abrogated fMLP-induced kappa B activity, These r esults suggest a potential role of fMLP in the transcription of proinflamma tory cytokines and provide the first evidence that such regulation may occu r through PI 3-kinase activity.