IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation
IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation
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DOI：
10.1038/nature03491
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发表时间：
2005-04-28
期刊：
影响因子：
64.8
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Lawrence, T;Bebien, M;Karin, M
炎症和先天免疫涉及导致炎症介质产生的信号通路。通常这种反应是自限的，但炎症的异常消解会导致慢性疾病(1)。很多注意力都集中在促炎信号上，但对消炎的机制知之甚少。I kappa B激酶(IKK)复合体包含两个催化亚基，即IKKα和IKKβ，控制着在炎症中起关键作用的核因子-kappaB转录因子的激活[2]。大量证据表明，IKKβ介导了促炎症细胞因子和微生物产物对核因子-kappaB的激活。IKKα调节对淋巴器官发生很重要的另一种途径(2)，但IKKα在炎症中的作用尚不清楚。在这里，我们描述了IKKα在巨噬细胞激活和炎症的负性调节中的新作用。IKKα通过加速核因子-kappa B亚单位relA和c-rel的周转，以及将其从促炎基因启动子中移除，从而有助于抑制核因子-kappaB的活性。在小鼠中，IKKα的失活可以增强炎症和细菌清除。因此，两个IKK催化亚基进化出了复杂的炎症控制和先天免疫所需的相反但互补的作用。
Inflammation and innate immunity involve signalling pathways leading to the production of inflammatory mediators. Usually such responses are self-limiting, but aberrant resolution of inflammation results in chronic diseases(1). Much attention has focused on pro-inflammatory signalling but little is known about the mechanisms that resolve inflammation. The I kappa B kinase (IKK) complex contains two catalytic subunits, IKK alpha and IKK beta, and controls the activation of NF-kappa B transcription factors, which play a pivotal role in inflammation(2). Ample evidence indicates that IKK beta mediates NF-kappa B activation in response to pro-inflammatory cytokines and microbial products. IKK alpha regulates an alternative pathway important for lymphoid organogenesis(2), but the role of IKK alpha in inflammation is unknown. Here we describe a new role for IKK alpha in the negative regulation of macrophage activation and inflammation. IKK alpha contributes to suppression of NF-kappa B activity by accelerating both the turnover of the NF-kappa B subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKK alpha in mice enhances inflammation and bacterial clearance. Hence, the two IKK catalytic subunits have evolved opposing but complimentary roles needed for the intricate control of inflammation and innate immunity.