Tumor necrosis factor-alpha-induced nuclear factor-kappa B signaling pathway (TNF-α/NF-κB pathway)

The Tumor necrosis factor-alpha-induced nuclear factor-kappa B signaling pathway is a central regulatory axis in the mammalian immune system, governing the expression of genes critical for inflammation, cell survival, and the innate immune response [1, 3]. The pathway is triggered by the binding of the cytokine Tumor necrosis factor-alpha (TNF-α) to its cognate receptors, primarily Tumor necrosis factor receptor 1 (TNFR1), which initiates the assembly of a multi-protein signaling complex [7, 10]. This complex activates the IκB kinase (IKK) complex, which subsequently phosphorylates the inhibitory protein IκBα, leading to its proteasomal degradation [6, 9]. The degradation of IκBα liberates the NF-κB transcription factor dimer, allowing it to translocate from the cytoplasm to the nucleus to drive the transcription of pro-inflammatory and anti-apoptotic genes [13, 18]. Dysregulation or constitutive activation of this pathway is strongly associated with chronic inflammatory conditions, such as rheumatoid arthritis and psoriasis, and plays a significant role in tumor promotion, survival, and metastasis in various cancers [4, 11, 15]. Therapeutic interventions targeting this pathway include TNF-α neutralizing agents, IKK inhibitors, and proteasome inhibitors, which aim to dampen excessive inflammatory signaling [6, 18, 20].

Other names

TNF-alpha/NF-kappaB axisCanonical NF-kappaB signaling pathwayTNFR1-mediated NF-kappaB activationTNF-induced NF-kappaB pathway

Neutralization of TNF-alpha, inhibition of IKK complex activation, prevention of IkappaB-alpha degradation, and blockade of NF-kappaB nuclear translocation.