Institute for Genetics, Centre for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany.
Cell Res. 2011 Jan;21(1):146-58. doi: 10.1038/cr.2010.175. Epub 2010 Dec 14.
The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.
IκB 激酶/NF-κB 信号通路与几种炎症性疾病的发病机制有关。在慢性炎症影响的组织中，免疫细胞和非免疫细胞中 NF-κB 的活性通常会增加，人们认为它通过诱导促炎介质的表达来发挥有害作用，从而协调和维持炎症反应并导致组织损伤。因此，NF-κB 激活增加被认为是许多急性和慢性炎症性疾病的重要致病因素，这增加了人们对 NF-κB 抑制剂可能有效治疗炎症性疾病的希望。然而，大量证据表明，NF-κB 抑制也可能对机体有害，并在某些情况下引发炎症和疾病的发展。这些发现表明，NF-κB 信号在维持生理免疫稳态和预防许多组织的炎症性疾病方面具有重要功能。这种 NF-κB 的有益功能主要在上皮细胞中观察到，表明 NF-κB 信号在维持上皮组织的免疫稳态方面具有特别重要的作用。因此，NF-κB 在慢性炎症中表现出两面性：一方面，增加和持续的 NF-κB 激活会引发炎症和组织损伤，但另一方面，NF-κB 信号的抑制也会干扰免疫稳态，引发炎症和疾病。在这里，我们讨论控制 NF-κB 信号这些明显相反功能的机制，特别关注 NF-κB 在调节肠道和皮肤中的免疫稳态和炎症中的作用。
