| First Author | Thapa RJ | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 14 | Pages | 2934-46 |
| PubMed ID | 21576359 | Mgi Jnum | J:174094 |
| Mgi Id | MGI:5051880 | Doi | 10.1128/MCB.05445-11 |
| Citation | Thapa RJ, et al. (2011) NF-{kappa}B Protects Cells from Gamma Interferon-Induced RIP1-Dependent Necroptosis. Mol Cell Biol 31(14):2934-46 |
| abstractText | 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-kappaB signaling. Induction of necroptosis by IFN-gamma was found to depend on Jak1 and partially on STAT1. We also demonstrate that IFN-gamma activates IkappaB kinase beta (IKKbeta)-dependent NF-kappaB 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-kappaB 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-kappaB protects cells from IFN-gamma-mediated necroptosis by transcriptionally activating a survival response that quenches ROS to preserve mitochondrial integrity. |
