NF-κB Protects Cells from Gamma Interferon-Induced RIP1-Dependent Necroptosis

Interferons (IFNs) are cytokines with well-described immunomodulatory and antiviral properties, but less is known about the mechanisms by which they promote cell survival or cell death. Here, we show that IFN-gamma induces RIP1 kinase-dependent necroptosis in mammalian cells deficient in NF-kappa B signaling. Induction of necroptosis by IFN-gamma was found to depend on Jak1 and partially on STAT1. We also demonstrate that IFN-gamma activates I kappa B kinase beta (IKK beta)-dependent NF-kappa B to regulate a transcriptional program that protects cells from necroptosis. IFN-gamma induced progressive accumulation of reactive oxygen species (ROS) and eventual loss of mitochondrial membrane potential in cells lacking the NF-kappa B subunit RelA. Whole-genome microarray analyses identified sod2, encoding the antioxidant enzyme manganese superoxide dismutase (MnSOD), as a RelA target and potential antinecroptotic gene. Overexpression of MnSOD inhibited IFN-gamma-mediated ROS accumulation and partially rescued RelA-deficient cells from necroptosis, while RNA interference (RNAi)-mediated silencing of sod2 expression increased susceptibility to IFN-gamma-induced cell death. Together, these studies demonstrate that NF-kappa B protects cells from IFN-gamma-mediated necroptosis by transcriptionally activating a survival response that quenches ROS to preserve mitochondrial integrity.