Nuclear Factor Kappa B Signaling Complexes in Acute Inflammation.

Significance: Nuclear factor kappa B (NF-κB) is a master regulator of the inflammatory response and represents a key regulatory node in the complex inflammatory signaling network. In addition, selective NF-κB transcriptional activity on specific target genes occurs through the control of redox-sensitive NF-κB interactions. Recent Advances: The selective NF-κB response is mediated by redox-modulated NF-κB complexes with ribosomal protein S3 (RPS3), Pirin (PIR). cAMP response element-binding (CREB)-binding protein (CBP)/p300, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), early growth response protein 1 (EGR-1), and SP-1. NF-κB is cooperatively coactivated with AP-1, STAT3, EGR-1, and SP-1 during the inflammatory process, whereas NF-κB complexes with CBP/p300 and PGC-1α regulate the expression of antioxidant genes. PGC-1α may act as selective repressor of phospho-p65 toward interleukin-6 (IL-6) in acute inflammation. p65 and nuclear factor erythroid 2-related factor 2 (NRF2) compete for binding to coactivator CBP/p300 playing opposite roles in the regulation of inflammatory genes. S-nitrosylation or tyrosine nitration favors the recruitment of specific NF-κB subunits to κB sites. Critical Issues: NF-κB is a redox-sensitive transcription factor that forms specific signaling complexes to regulate selectively the expression of target genes in acute inflammation. Protein-protein interactions with coregulatory proteins, other transcription factors, and chromatin-remodeling proteins provide transcriptional specificity to NF-κB. Furthermore, different NF-κB subunits may form distinct redox-sensitive homo- and heterodimers with distinct affinities for κB sites. Future Directions: Further research is required to elucidate the whole NF-κB interactome to fully characterize the complex NF-κB signaling network in redox signaling, inflammation, and cancer.