Prostaglandin F2α (PGF2α) stimulation of tumor necrosis factor‐α (TNF‐α) promoter activity by sequential activation of protein kinase C (PKC) and nuclear factor‐κB (NF‐κB) signaling

Abstract

TNF‐α is a cytokine that promotes inflammation and apoptosis. Over production of TNF‐α in microglia, the resident macrophages in the brain, causes neuronal death and has been linked to inflammatory neurological disorders such as Alzheimer's disease. Another signaling molecule up regulated during inflammation is PGF2α, which activates intracellular Ca2+ and PKC signaling through the Gq‐coupled FP prostanoid receptor. The specific role, however, of PGF2α in the promotion of inflammation by TNF‐α is not well understood. In this study, we hypothesized that activation of the human FP receptor by PGF2α can stimulate the activity of the TNF‐α gene promoter. In support of this hypothesis PGF2α stimulated TNF‐α promoter activity in cultured microglia transfected with a reporter plasmid controlled by the TNF‐α promoter; similar results were obtained with HEK‐293 cells stably expressing the FP receptor. The TNF‐α promoter contains a NF‐κB binding site and inhibition of NF‐κB reduced PGF2α stimulated TNF‐α promoter activity. Additionally, inhibition of PKC decreased the activity of reporter genes under the control of either NF‐κB or TNF‐α, respectively. These results indicate that PGF2α acts through the FP receptor to induce TNF‐α promoter activity by a mechanism involving the PKC dependent activation of NF‐κB. We believe this mechanism helps provide a better understanding of the role of PGF2α in inflammatory diseases.