NF-κB signaling in inflammation

Abstract

The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.

Figure 1

NF-κB target genes involved in inflammation development and progression. NF-κB is an inducible transcription factor. After its activation, it can activate transcription of various genes and thereby regulate inflammation. NF-κB target inflammation not only directly by increasing the production of inflammatory cytokines, chemokines and adhesion molecules, but also regulating the cell proliferation, apoptosis, morphogenesis and differentiation.

Figure 2

NF-κB in the regulation of NLRP3 inflammasome. The activation of NLRP3 inflammasome requires two signals, priming and activation. A prototypical example of priming is bacterial LPS binding to TLR4, leading to the activation of NF-κB signaling. In the nucleus, the active NF-κB promotes the transcription of NF-κB-dependent genes, such as NLRP3, Pro-IL-1β and Pro-IL-18, which are necessary for inflammasome activation. The second signal of inflammasome activation is provided by NLRP3 agonists that activates NLRP3 to trigger inflammasome assembly and mature IL-1β secretion. To date, mitochondrial damage is the most widely studied activating stimuli for NLRP3 pathway in terms of its connection to diverse inflammatory, metabolic and malignant diseases. NF-κB induces delayed accumulation of the autophagy receptor p62, which can specifically bind to mitochondrial poly-ubiquitin chains though E3 ubiquitin ligase Parkin, and thereby, negatively regulate inflammasome activation via mitophagic elimination.

Figure 3

NF-κB-targeted therapeutics in inflammatory diseases. NF-κB signaling plays a pathogenic role in various inflammatory diseases; therefore, there are many therapeutic strategies for inflammatory diseases aimed at blocking NF-κB activity. First, inhibition of IKK kinase activity. Drugs such as aspirin and salicylate have the ability to specifically inhibit IKK, thereby preventing phosphorylation of IκBα. Second, inhibition of protease activity. Drugs such as PS-341 and lactacystin specifically inhibit 26S proteasome complex, thereby preventing IκBα degradation. Third, inhibition of nuclear translocation. Drugs such as tacrolimus and IκBα super-repressor specifically prevent NF-κB subunits RelA, p50, c-Rel and other members from entering the nucleus. Finally, inhibition of DNA binding. Drugs such as glucocorticoids and PPAR agonists have the ability to prevent NF-κB subunits from binging with target genes, and therefore inhibit the transcription.