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 human peripheral blood monocytes is an important component of the inflammatory process. The signaling mechanisms used by fMLP to stimulate the release of cytokines are still incompletely understood. We previously demonstrated that fMLP-stimulated NF-kappaB activation in PBMC and now we present evidence that the lipid products of phosphatidylinositol 3-kinase (PI 3-kinase) are required for fMLP-stimulated activation of NF-kappaB. Pretreatment with the PI 3-kinase inhibitors, wortmannin and LY294002, effectively blocked fMLP-induced IL-1beta gene expression as well as NF-kappaB activation. Transient transfection of THP1 cells with a dominant-negative mutant of the PI 3-kinase p85 subunit also abrogated fMLP-induced kappaB activity. These results suggest a potential role of fMLP in the transcription of proinflammatory cytokines and provide the first evidence that such regulation may occur through PI 3-kinase activity.