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

Abstract

During inflammation, NF-κB transcription factors antagonize apoptosis induced by tumor necrosis factor (TNF)α. This antiapoptotic activity of NF-κB 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-κB 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-κB. FHC is induced downstream of NF-κB and is required to prevent sustained JNK activation and, thereby, apoptosis triggered by TNFα. 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-κB-mediated control of ROS induction and identify a mechanism by which NF-κB suppresses proapoptotic JNK signaling. Our results suggest modulation of FHC or, more broadly, of iron metabolism as a potential approach for anti-inflammatory therapy.