Toll-like receptor 4 (TLR4)–Nuclear factor kappa B (NF-κB) signaling pathway (TLR4–NF-κB pathway)

The Toll-like receptor 4 (TLR4)–Nuclear factor kappa B (NF-κB) signaling pathway is a fundamental axis of the innate immune system that mediates the inflammatory response to Gram-negative bacterial infections and endogenous danger signals (StatPearls, "Toll Like Receptor 4"). Activation begins when Toll-like receptor 4, in complex with MD-2 and CD14, recognizes lipopolysaccharide (LPS), triggering the recruitment of intracellular adapter proteins like MyD88 and TRIF (UniProt O00206). This recruitment initiates a kinase cascade that culminates in the activation of the IκB kinase (IKK) complex, which phosphorylates IκB, leading to its proteasomal degradation and the subsequent nuclear translocation of NF-κB (UniProt P19838). Once in the nucleus, NF-κB promotes the transcription of numerous genes involved in inflammation, such as TNF-α, IL-1β, and IL-6 (PubMed PMID 30107265). Chronic or excessive activation of this pathway is a hallmark of conditions like sepsis, rheumatoid arthritis, and various cancers, making it a prime target for therapeutic intervention (PubMed PMID 28638113). Drugs targeting this pathway include TLR4 antagonists like Resatorvid and various inhibitors that prevent NF-κB activation, aimed at dampening pathological inflammation (PubChem CID 11682024).

Other names

TLR4/NF-kappaB axisTLR4-mediated NF-kappaB activationLPS-induced TLR4 signalingTLR4-NF-kappaB signaling

Inhibition of TLR4-ligand binding, inhibition of IKK complex activation, or prevention of NF-κB nuclear translocation to suppress pro-inflammatory gene expression.