NF-κB:: a key role in inflammatory diseases
NF-κB:: a key role in inflammatory diseases
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DOI：
10.1172/jci11830
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发表时间：
2001-01-01
影响因子：
15.9
通讯作者：
Firestein, GS
中科院分区：
文献类型：
--
作者：
Tak, PP;Firestein, GS
NF-κB在防御和疾病丝氨酸残基。磷酸化的IκBα随后被泛素化，靶向其被26 S蛋白酶体降解（13），从而从细胞质NF-κB-IκB复合物中释放NF-κB二聚体，并使其易位至细胞核。然后NF-κB与靶基因的κB增强子元件结合，诱导促炎基因的转录。IKK还磷酸化IκBβ和IκBε。IκBβ的磷酸化导致NF-κB活化延长（14），这可以部分解释为降解后IκBβ再合成延迟。与IκBβ一样，IκBε以相对缓慢的动力学降解，但其也可能以与IκBα相当的速率再合成。在许多细胞类型中，IKK位于导致NF-κB激活的多种信号传导途径的关键会聚位点（15）。IKK-β敲除小鼠由于肝细胞凋亡而发生肝衰竭，尤其是在TNF-α存在的情况下（16）。尽管NF-κB阻断在胚胎发育期间似乎具有肝毒性，但使用诱导型IκBα超阻遏物转基因表明NF-κB抑制在成年小鼠中耐受良好（17）。然而，即使在该模型中，NF-κB阻断也会损害正常的宿主防御，使小鼠无法清除单核细胞增生李斯特菌的机会性感染。IKK-α基因敲除显示异常形态发生。IKK-α似乎参与角质形成细胞分化和表皮形成（18）。
NF-κB in defense and disease serine residues. Phosphorylated IκBα is then ubiquitinated, which targets it for degradation by the 26S proteasome (13), thereby releasing NF-κB dimers from the cytoplasmic NF-κB–IκB complex and allowing them to translocate to the nucleus. NF-κB then binds to κB enhancer elements of target genes, inducing transcription of proinflammatory genes. IKK also phosphorylates IκBβ and IκBε. Phosphorylation of IκBβ leads to prolonged NF-κB activation (14), which can in part be explained by the delay in IκBβ resynthesis after degradation. IκBε is degraded with relatively slow kinetics like IκBβ, but it may also be resynthesized at a rate comparable with that of IκBα.In many cell types, IKK resides at a key convergence site for multiple signaling pathways that lead to NF-κB activation (15). IKK-β knockout mice develop liver failure due to hepatocyte apoptosis, especially in the presence of TNF-α (16). Although NF-κB blockade appears to be hepatotoxic during embryonic development, the use of an inducible IκBα super-repressor transgene suggests that NF-κB inhibition is well tolerated in adult mice (17). However, even in that model, NF-κB blockade compromises normal host defense and leaves mice unable to clear opportunistic infections with Listeria monocytogenes. IKK-α knockouts exhibit abnormal morphogenesis. IKK-α appears to be involved in keratinocyte differentiation and formation of the epidermis (18).