Master inflammation + survival transcription factor pathway. Resting state: NF-κB heterodimer (p50/p65) sequestered in cytoplasm bound to IκB. Activation by TLR / TNF / IL-1 / antigen receptor signaling → IKK complex phosphorylates IκB → IκB ubiquitinated + proteasomally degraded → NF-κB translocates to nucleus → drives transcription of cytokines (TNF, IL-6, IL-1β), adhesion molecules, anti-apoptotic genes (BCL-2 family), COX-2, iNOS. Glucocorticoids inhibit NF-κB via transrepression (GR-NF-κB direct interaction) — the explanation for their broad anti-inflammatory action. NSAIDs work downstream (block COX-2 product); steroids work upstream.
Organ Systems
immune-hematologic
nervous
Pathway Steps
tnf-alpha → ikk-activation — via TNFR1 → TRADD → TRAF2 → RIP → IKK complex. This is the canonical pathway: TNF→TNFR1 assembles a TRADD/TRAF2/RIP1 complex that activates the IKK complex (IKKα/IKKβ/NEMO). A parallel non-canonical pathway (NIK→IKKα, from BAFF/lymphotoxin receptors) instead processes p100→p52 for lymphoid-organ development; RIP1 is also the switch toward apoptosis/necroptosis when NF-κB fails.
ikk-activation → ikb-degradation — via IκB phosphorylation → ubiquitination → 26S proteasome. IKKβ phosphorylates IκB, marking it for β-TrCP ubiquitination and proteasomal degradation — the step that frees NF-κB. IKKβ is the target of high-dose salicylates and many anti-inflammatories, and proteasome inhibitors (bortezomib) act partly by blocking IκB degradation, keeping NF-κB off.
ikb-degradation → nfkb-nuclear — via released NF-κB heterodimer translocates to nucleus. With IκB destroyed, the unmasked nuclear localization signal lets the p65/p50 (RelA) heterodimer enter the nucleus. NF-κB drives its own inhibitor IκBα as a target gene — a negative-feedback loop that yields oscillatory, pulsatile activity rather than a sustained on-state.
nfkb-nuclear → inflammatory-cytokines — via transcriptional activation of TNF / IL-6 / IL-1β / COX-2 / iNOS. NF-κB is the master transcriptional switch of inflammation/immunity, inducing TNF, IL-6, IL-1β, COX-2, iNOS, and anti-apoptotic genes — a feed-forward amplifier (TNF induces more NF-κB). Its pro-survival output also makes constitutive NF-κB a driver of inflammation-associated cancer and chemoresistance.
Known Modulators
prednisone (inhibitor) — NF-κB transrepression via GR (broad downstream effect)
dexamethasone (inhibitor) — NF-κB transrepression via GR