Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Oct 30;11:407-419.
doi: 10.2147/JIR.S140188. eCollection 2018.

Mechanisms of NF-κB p65 and Strategies for Therapeutic Manipulation

Affiliations
Free PMC article
Review

Mechanisms of NF-κB p65 and Strategies for Therapeutic Manipulation

Sivagami Giridharan et al. J Inflamm Res. .
Free PMC article

Abstract

The transcription factor NF-κB is a critical regulator of immune and inflammatory responses. In mammals, the NF-κB/Rel family comprises five members: p50, p52, p65 (Rel-A), c-Rel, and Rel-B proteins, which form homo- or heterodimers and remain as an inactive complex with the inhibitory molecules called IκB proteins in resting cells. Two distinct NF-κB signaling pathways have been described: 1) the canonical pathway primarily activated by pathogens and inflammatory mediators, and 2) the noncanonical pathway mostly activated by developmental cues. The most abundant form of NF-κB activated by pathologic stimuli via the canonical pathway is the p65:p50 heterodimer. Disproportionate increase in activated p65 and subsequent transactivation of effector molecules is integral to the pathogenesis of many chronic diseases such as the rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and even neurodegenerative pathologies. Hence, the NF-κB p65 signaling pathway has been a pivotal point for intense drug discovery and development. This review begins with an overview of p65-mediated signaling followed by discussion of strategies that directly target NF-κB p65 in the context of chronic inflammation.

Keywords: NF-κB; inflammation; therapy.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Model for basal and induced NF-κB p65 activity. Notes: Basal NF-κB activity is potentially maintained by a balanced shuttling of the NF-κB p65:IκB complex between the cytoplasm and nucleus. In a steady-state condition, IκBα masks entirely the nuclear localization signal of p65 but not that of p50. This allows shuttling of the NF-κB:IκB complex by passive nuclear import to support basal activity and reciprocal export by the nuclear export signals in the terminal ankyrin repeat of IκBα. Stimulus induced phosphorylation of IKKβ followed by protein kinase-A-mediated phosphorylation of IκBα and rapid release and import of p65:p50 dimers. Postinduction, the newly synthesized IκBα not only sequesters DNA bound p65 but also shuttles to the cytoplasm to quench the free p50:p65 dimers.
Figure 2
Figure 2
Schematic representation of NF-κB p65 activation and potential inhibitors along the signaling pathway. Notes: The inset shows phosphorylation and acetylation sites of p65 as sites of kinase inhibitors and HDACs. Representative inhibitory strategies along the pathway are shown. Abbreviations: NBD, NeMO binding peptide; GC, glucocorticoid; GILZ, glucocorticoid-induced leucine zipper; GR, glucocorticoid receptor; HDAC, histone deacytelases; NLS, nuclear localization signal; ODN, oligodeoxynucleotide; PCAF, p300/CBP-associated factor; TAD, transactivation domain.

Similar articles

See all similar articles

Cited by 16 articles

See all "Cited by" articles

References

    1. Basak S, Behar M, Hoffmann A. Lessons from mathematically modeling the NF-κB pathway. Immunol Rev. 2012;246(1):221–238. - PMC - PubMed
    1. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1(4):a000034. - PMC - PubMed
    1. Karin M, Yamamoto Y, Wang QM. The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov. 2004;3(1):17–26. - PubMed
    1. Christian F, Smith E, Carmody R. The regulation of NF-κB subunits by phosphorylation. Cells. 2016;5(1):12. - PMC - PubMed
    1. Razani B, Zarnegar B, Ytterberg AJ, et al. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci Signal. 2010;3(123):ra41. - PMC - PubMed
Feedback