Ferritin Heavy Chain Upregulation by NF-κB Inhibits TNFα-Induced Apoptosis by Suppressing Reactive Oxygen Species

al., 2002). Cytotoxicity caused by ROS is mediated in part by the JNK pathway (Matsuzawa et al., 2002). Acti-During inflammation, NF-␬B transcription factors an-vation of this pathway by TNF␣ promotes death by in-tagonize apoptosis induced by tumor necrosis factor ducing cleavage of the Bcl-2 family BH3-only protein, (TNF)␣. This antiapoptotic activity of NF-␬B involves Bid, into jBid, which targets mitochondria to trigger re-suppressing the accumulation of reactive oxygen spe-lease of Smac/Diablo into cytosol, leading to activation cies (ROS) and controlling the activation of the c-Jun of caspase-8 (Deng et al., 2003). ROS can also mediate N-terminal kinase (JNK) cascade. However, the mech-caspase-independent, necrosis-like cell death (Leist anism(s) by which NF-␬B inhibits ROS accumulation and Jaattela, 2001). is unclear. We identify ferritin heavy chain (FHC)—the In eukaryotes, the main source of oxygen radicals is primary iron storage factor—as an essential mediator mitochondria (Curtin et al., 2002; Fleury et al., 2002). of the antioxidant and protective activities of NF-␬B. Here, molecular oxygen is converted into superoxide FHC is induced downstream of NF-␬B and is required anion (O 2 .Ϫ), a moderately reactive species capable of to prevent sustained JNK activation and, thereby, apo-generating hydrogen peroxide (H 2 O 2), which in turn can ptosis triggered by TNF␣. FHC-mediated inhibition of produce highly reactive hydroxyl radicals (·OH) via JNK signaling depends on suppressing ROS accumu-metal-dependent breakdown (Curtin et al., 2002). Cells lation and is achieved through iron sequestration. possess effective mechanisms to control ROS. Among These findings establish a basis for the NF-␬B-medi-these is the synthesis of enzymes such as superoxide ated control of ROS induction and identify a mecha-dismutases (SODs), catalase, and glutathione peroxi-nism by which NF-␬B suppresses proapoptotic JNK dases (Gpxs), which convert ROS into less-active spe-signaling. Our results suggest modulation of FHC or, cies (Curtin et al., 2002; Fleury et al., 2002). Another more broadly, of iron metabolism as a potential ap-powerful strategy that cells have adopted to overcome proach for anti-inflammatory therapy. ROS is to limit the cellular availability of transition metals , most notably iron. Indeed, this metal catalyzes the Introduction generation of O 2 .Ϫ in mitochondria and participates in Fenton and Haber-Weiss reactions leading to formation In addition to marshalling immune and inflammatory re-of ·OH (Curtin et al., 2002; Torti and Torti, 2002). This sponses, NF-␬B transcription factors control apoptosis control of iron levels is achieved in part through metal or programmed cell death (PCD) (Kucharczak …