NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ
NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ
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DOI：
10.1016/j.cell.2007.07.009
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发表时间：
2007-09-07
期刊：
影响因子：
64.5
通讯作者：
Karin, Michael
中科院分区：
文献类型：
--
作者：
Greten, Florian R.;Arkan, Melek C.;Karin, Michael
IKK β依赖的NF-kappa B激活在先天免疫和炎症中起关键作用，抑制IKK β被认为是一种可能的抗炎治疗方法。然而，令人惊讶的是，髓细胞中靶向IKK β缺失的小鼠比对照小鼠更容易受到内毒素诱导的休克。内毒素敏感性增加与血浆IL-1 β升高有关，这是由于前IL-1 β加工增加的结果，在细菌感染中也可以看到。在巨噬细胞中，增强的亲il -1 β加工依赖于caspase-1，其激活被nf - κ b依赖性基因产物抑制。然而，在中性粒细胞中，IL-1 β的分泌是caspase-1独立的，依赖于丝氨酸蛋白酶，丝氨酸蛋白酶的活性也被NF-kappa B基因产物抑制。长期的药物抑制IKK β也增加内毒素攻击时IL-1 β的分泌。这些结果揭示了IKK β依赖的NF-kappa B信号在IL-1 β产生的阴性控制中的一个意想不到的作用，并强调了长期IKK β抑制的潜在并发症。
IKK beta-dependent NF-kappa B activation plays a key role in innate immunity and inflammation, and inhibition of IKK beta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKK beta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1 beta as a result of increased pro-IL-1 beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1 beta processing depends on caspase-1, whose activation is inhibited by NF-kappa B-dependent gene products. In neutrophils, however, IL-1 beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappa B gene products. Prolonged pharmacologic inhibition of IKK beta also augments IL-1 beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKK beta-dependent NF-kappa B signaling in the negative control of IL-1 beta production and highlight potential complications of long-term IKK beta inhibition.