Tumor necrosis factor-driven nuclear factor-kappa B signaling pathway (TNF-NF-κB pathway)

The Tumor Necrosis Factor (TNF)-driven Nuclear Factor-kappa B (NF-κB) signaling pathway is a central molecular axis that orchestrates inflammatory and immune responses. It is triggered by the binding of TNF-alpha to its receptors, TNFR1 and TNFR2, which initiates the assembly of a signaling complex involving adaptors like TRADD and RIPK1. This complex activates the IκB kinase (IKK) complex, leading to the phosphorylation and subsequent proteasomal degradation of the inhibitory protein IκB. The release of NF-κB dimers allows their translocation into the nucleus, where they drive the expression of genes critical for inflammation, cell survival, and proliferation [nih.gov, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551225/]. Dysregulation of this pathway is implicated in a wide range of pathologies, including rheumatoid arthritis, inflammatory bowel disease, and various cancers [mdpi.com, https://www.mdpi.com/1422-0067/21/17/6126]. Therapeutic strategies often focus on neutralizing TNF-alpha or inhibiting downstream kinases to mitigate chronic inflammation, though these interventions carry risks of immunosuppression and infection [nih.gov, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515013/]. While this pathway is a major focus of drug development, it represents a signaling network rather than a single molecular target.

Other names

TNF-NFkB axisTNF-induced NF-kappaB activationCanonical NF-kappaB signaling pathwayTNF-TNFR-NF-kappaB pathway

Therapeutic agents target this pathway by neutralizing the TNF-alpha ligand to prevent receptor binding (e.g., infliximab, adalimumab) or by inhibiting the proteasomal degradation of IκB (e.g., bortezomib), thereby preventing the nuclear translocation of NF-κB transcription factors and the subsequent expression of pro-inflammatory genes [nih.gov, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551225/].