Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor a gene induction

Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a signaling pathway involving the activation of phospholipase A₂ and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor α gene. Treatment of human cells with ionizing radiation or H₂O₂ was associated with the production of arachidonic acid. Inhibition of phospholipase A₂ abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor α gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A₂ inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor α production.