Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species

During inflammation, NF-kappaB transcription factors antagonize apoptosis induced by tumor necrosis factor (TNF)alpha. This antiapoptotic activity of NF-kappaB involves suppressing the accumulation of reactive oxygen species (ROS) and controlling the activation of the c-Jun N-terminal kinase (JNK) c...

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Bibliographic Details
Published in:Cell 2004-11, Vol.119 (4), p.529-542
Main Authors: Pham, Can G, Bubici, Concetta, Zazzeroni, Francesca, Papa, Salvatore, Jones, Joy, Alvarez, Kellean, Jayawardena, Shanthi, De Smaele, Enrico, Cong, Rong, Beaumont, Carole, Torti, Frank M, Torti, Suzy V, Franzoso, Guido
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Ferritins - metabolism
Gene Expression Regulation
HeLa Cells
Humans
Inflammation - metabolism
JNK Mitogen-Activated Protein Kinases - metabolism
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinase Kinases - metabolism
NF-kappaB-Inducing Kinase
Protein Serine-Threonine Kinases - pharmacology
Reactive Oxygen Species - metabolism
Signal Transduction
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Up-Regulation
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Summary:During inflammation, NF-kappaB transcription factors antagonize apoptosis induced by tumor necrosis factor (TNF)alpha. This antiapoptotic activity of NF-kappaB involves suppressing the accumulation of reactive oxygen species (ROS) and controlling the activation of the c-Jun N-terminal kinase (JNK) cascade. However, the mechanism(s) by which NF-kappaB inhibits ROS accumulation is unclear. We identify ferritin heavy chain (FHC)--the primary iron storage factor--as an essential mediator of the antioxidant and protective activities of NF-kappaB. FHC is induced downstream of NF-kappaB and is required to prevent sustained JNK activation and, thereby, apoptosis triggered by TNFalpha. FHC-mediated inhibition of JNK signaling depends on suppressing ROS accumulation and is achieved through iron sequestration. These findings establish a basis for the NF-kappaB-mediated control of ROS induction and identify a mechanism by which NF-kappaB suppresses proapoptotic JNK signaling. Our results suggest modulation of FHC or, more broadly, of iron metabolism as a potential approach for anti-inflammatory therapy.
ISSN:0092-8674