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Thapa RJ , Basagoudanavar SH , Nogusa S , Irrinki K , Mallilankaraman K , Slifker MJ , Beg AA , Madesh M , Balachandran S
NF-kappa B Protects Cells from Gamma Interferon-Induced RIP1-Dependent Necroptosis
Molecular and Cellular Biology. 2011 Jul;31(14) :2934-2946
PMCID: PMC3133390   
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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.
Thapa, Roshan J. Basagoudanavar, Suresh H. Nogusa, Shoko Irrinki, Krishna Mallilankaraman, Karthik Slifker, Michael J. Beg, Amer A. Madesh, Muniswamy Balachandran, Siddharth Amer soc microbiology Washington 784ic