title: NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis.
abstract: 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-γ induces RIP1 kinase-dependent necroptosis in mammalian cells deficient in NF-κB signaling. Induction of necroptosis by IFN-γ was found to depend on Jak1 and partially on STAT1. We also demonstrate that IFN-γ activates IκB kinase β (IKKβ)-dependent NF-κB to regulate a transcriptional program that protects cells from necroptosis. IFN-γ induced progressive accumulation of reactive oxygen species (ROS) and eventual loss of mitochondrial membrane potential in cells lacking the NF-κB 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-γ-mediated ROS accumulation and partially rescued RelA-deficient cells from necroptosis, while RNA interference (RNAi)-mediated silencing of sod2 expression increased susceptibility to IFN-γ-induced cell death. Together, these studies demonstrate that NF-κB protects cells from IFN-γ-mediated necroptosis by transcriptionally activating a survival response that quenches ROS to preserve mitochondrial integrity.
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.forename: Suresh H
authors.initials: SH
authors.lastname: Basagoudanavar
authors.forename: Shoko
authors.initials: S
authors.lastname: Nogusa
authors.forename: Krishna
authors.initials: K
authors.lastname: Irrinki
authors.forename: Karthik
authors.initials: K
authors.lastname: Mallilankaraman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Slifker
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
chemical_list: D051550:I-kappa B Kinase; D007371:Interferon-gamma; D053613:Janus Kinase 1; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D050794:STAT1 Transcription Factor; D013482:Superoxide Dismutase; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099156:Superoxide Dismutase 2