NF-κB Inflammatory Signaling

Nuclear Factor kappa-B is a master transcription factor controlling inflammation, immune response, cell survival, and proliferation. Chronic activation drives neuroinflammation and tumor-promoting inflammation.

Overview

In resting cells, NF-κB dimers (p65/p50) are sequestered in the cytoplasm by IκB inhibitors. Upon stimulation by TNF-α, IL-1β, LPS, or oxidative stress, the IKK complex phosphorylates IκBα, marking it for proteasomal degradation. Released NF-κB translocates to the nucleus and activates transcription of pro-inflammatory genes (COX-2, iNOS, TNF-α, IL-6, IL-8), anti-apoptotic genes (Bcl-2, XIAP), and proliferation genes (Cyclin D1, c-Myc).

Key Steps

1. TNF-α/IL-1β bind membrane receptors, recruiting TRAF adaptor proteins
2. IKK complex (IKKα, IKKβ, NEMO) is activated via ubiquitin signaling
3. IKKβ phosphorylates IκBα at Ser32/36, triggering K48-linked ubiquitination
4. Proteasomal degradation of IκBα exposes NF-κB nuclear localization signal
5. NF-κB translocates to nucleus, binds κB enhancer elements in target gene promoters
6. Negative feedback: NF-κB induces IκBα transcription, re-sequestering NF-κB

Disease Relevance

• Cancer: Constitutive NF-κB activation is found in ~95% of cancers. It promotes survival, proliferation, angiogenesis, and metastasis. It drives chemoresistance by upregulating anti-apoptotic genes.
• ALS: NF-κB-mediated neuroinflammation in microglia and astrocytes accelerates motor neuron death. Targeting NF-κB is a therapeutic strategy for slowing ALS progression.
• Alzheimer's: NF-κB is elevated in AD brains. Amyloid-β activates NF-κB in microglia, creating a feed-forward inflammatory loop that worsens neurodegeneration.

Therapeutic Targets

• Curcumin: Directly inhibits IKKβ kinase activity and NF-κB DNA binding
• Sulforaphane: Inhibits NF-κB via Nrf2-mediated antioxidant response
• Resveratrol: SIRT1-dependent deacetylation of NF-κB p65 subunit
• EGCG: Suppresses IKK activation and NF-κB nuclear translocation