Ferritin heavy chain upregulation by NF-κB inhibits TNFα-induced apoptosis by suppressing reactive oxygen species
Ferritin heavy chain upregulation by NF-κB inhibits TNFα-induced apoptosis by suppressing reactive oxygen species
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DOI：
10.1016/j.cell.2004.10.017
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发表时间：
2004-11-12
期刊：
影响因子：
64.5
通讯作者：
Franzoso, G
中科院分区：
文献类型：
--
作者：
Pham, CG;Bubici, C;Franzoso, G
在炎症过程中，NF-κ B转录因子拮抗肿瘤坏死因子（TNF）α诱导的细胞凋亡。NF-κ B的这种抗凋亡活性涉及抑制活性氧（ROS）的积累和控制c-Jun N-末端激酶（JNK）级联的激活。然而，NF-κ B抑制ROS积累的机制尚不清楚。我们确定铁蛋白重链（FHC）-主要的铁储存因子-作为NF-κ B的抗氧化和保护活性的重要介质。FHC在NF-κ B的下游被诱导，并且是防止持续的JNK激活所必需的，从而防止由TNF α触发的细胞凋亡。FHC介导的JNK信号转导抑制依赖于抑制ROS积累，并通过铁螯合实现。这些发现为NF-κ B介导的ROS诱导控制奠定了基础，并确定了NF-κ B抑制促凋亡JNK信号传导的机制。我们的研究结果表明，FHC或更广泛地说，铁代谢的调制作为一种潜在的抗炎治疗方法。
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.