Nuclear factor kappa B (NF-κB)-dependent tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) signaling pathway components (NF-κB/TNF-α/IL-1β pathway)

The NF-κB–dependent TNF-α and IL-1β signaling pathway components represent a complex network of proteins that mediate the cellular response to pro-inflammatory stimuli. Activation begins when the cytokines Tumor Necrosis Factor-alpha (TNF-α) or Interleukin-1 beta (IL-1β) bind to their cognate receptors, triggering a signal transduction cascade that involves various adapter proteins and kinases (Liu et al., 2017 [1]; Hayden & Ghosh, 2014 [2]). The central node of this pathway is the IκB kinase (IKK) complex, which phosphorylates the inhibitory IκB protein, leading to its ubiquitination and degradation by the proteasome (Liu et al., 2017 [1]). This process releases the transcription factor NF-κB, allowing it to move into the nucleus and initiate the transcription of genes involved in inflammation, immune regulation, and cell survival (Hayden & Ghosh, 2014 [2]). Aberrant signaling within this pathway is a hallmark of many autoimmune and autoinflammatory diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease, as well as certain types of cancer (Dinarello, 2011 [3]). Therapeutic strategies targeting these components include monoclonal antibodies that neutralize the cytokines, decoy receptors, and small molecules that inhibit the kinases or the proteasome (Dinarello, 2011 [3]). Sources: [1] Liu, T., et al. (2017) 'NF-κB signaling in inflammation', Signal Transduction and Targeted Therapy; [2] Hayden, M. S., & Ghosh, S. (2014) 'Regulation of NF-κB by TNF family cytokines', Seminars in Immunology; [3] Dinarello, C. A. (2011) 'Interleukin-1 in the pathogenesis and treatment of inflammatory diseases', Blood.

Other names

NF-kappaB signaling pathwayTNF-alpha/IL-1beta-mediated NF-kappaB activationPro-inflammatory cytokine signaling pathwayCanonical NF-kappaB pathway

Inhibition of cytokine-receptor binding (e.g., TNF-alpha or IL-1 beta neutralization), inhibition of the IKK complex activity, or inhibition of the 26S proteasome to prevent IκB degradation and subsequent NF-κB nuclear translocation.