The NF-κB signaling pathway is not required for fas ligand gene induction but mediates protection from activation-induced cell death

Abstract

Stimulation of T cells by antigens or mitogens triggers multiple signaling pathways leading to activation of genes encoding interleukin-2 and other growth-regulatory cytokines. The same stimuli also activate the gene encoding an apoptosis-inducing molecule, Fas ligand (FasL), which contributes to activation-induced cell death. It has been proposed that the signaling pathways involved in cytokine gene induction also contribute to activation-induced FasL expression; however, genetic evidence for this proposal is lacking. In the present study, the role of the NF-κB signaling pathway in FasL gene expression was examined using a mutant T cell line deficient in an essential NF-κB signaling component, IκB kinase γ. These mutant cells have a blockade in signal-induced activation of NF-κB but remained normal in the activation of NF-AT and AP-1 transcription factors. Interestingly, the NF-κB signaling defect has no effect on mitogen-stimulated FasL gene expression, although it completely blocks the interleukin-2 gene induction. We further demonstrate that NF-κB activation is required for protecting T cells from apoptosis induction by mitogens and an agonistic anti-Fas antibody. These genetic results suggest that the NF-κB signaling pathway is not required for activation-induced FasL expression but rather mediates cell growth and protection from activation-induced cell death.