NF-κB in inflammation and renal diseases

Abstract

Nuclear factor κB (NF-κB) is a family of inducible transcription factors that plays a vital role in different aspects of immune responses. NF-κB is normally sequestered in the cytoplasm as inactive complexes via physical association with inhibitory proteins termed IκBs. In response to immune and stress stimuli, NF-κB members become activated via two major signaling pathways, the canonical and noncanonical pathways, and move to the nucleus to exert transcriptional functions. NF-κB is vital for normal immune responses against infections, but deregulated NF-κB activation is a major cause of inflammatory diseases. Accumulated studies suggest the involvement of NF-κB in the pathogenesis of renal inflammation caused by infection, injury, or autoimmune factors. In this review, we discuss the current understanding regarding the activation and function of NF-κB in different types of kidney diseases.

Keywords: IgA nephropathy; Inflammation; NF-κB; Nephritis; Renal diseases.

Fig. 1

The mammalian NF-κB and IκB families. The five members of the NF-κB family are schematically shown, with the major domains highlighted and the alternative names indicated in parenthes. The rel-homology domain (RHD) mediates DNA-binding and dimerization functions, the transactivation domain (TD) is required for transcriptional activation of target genes, whereas the leucine zipper (LZ) motif is also involved in target gene transactivation. The IκB family includes the p50 precursor protein p105, the p52 precursor protein p100, IκBα, IκBβ, IκBε, and several atyipical IκB members that are not shown in the figure. A hallmark of IκB members if the presence of ankyrin repeats that are required for inhibition of NF-κB. The death domain (DD) of p105 and p100 is also important for their IκB-like functions. The PEST (proline, glutamine, serine, and threonine)-like sequence of IκBα and IκBβ mediates protein turnover. RHD rel-homology domain, TD transactivation domain, LZ leucine zipper, DD death domain, PEST proline, glutamine, serine, and threonine

Fig. 2

Canonical and noncanonical NF-κB signaling pathways. The canonical NF-κB pathway responds to signals from diverse receptors, including pattern-recognition receptors (PRRs) present on cell surface or intracellular environment, TNF receptors (TNFRs), other cytokine receptors, as well as T cell receptor (TCR) and B cell receptor (BCR). The noncanonical NF-κB pathway is activated by a selective subset of TNFR superfamily members. Canonical NF-κB signaling involves activation of the trimeric IKK complex by the MAP3 K TAK1, IKK-mediated IκBα phosphorylation and subsequent degradation, and nuclear translocation of the prototypical NF-κB heterodimer RelA/p50. Noncanonical NF-κB signaling relies on NF-κB inducing kinase (NIK), which together with IKKα mediate phosphorylation and processing of p100, causing generation of p52 and nuclear translocation of p52/RelB complex. Compared with the pleotropic roles of canonical pathway, noncanonical NF-κB has more specific functions. PRR pattern-recognition receptors, TNFR TNF receptor, TCR T cell receptor, BCR B cell receptor, NIK NF-κB inducing kinase