MyD88-dependent NF-kappaB signaling pathway (MyD88/NF-kB pathway)

The MyD88-dependent NF-kappaB signaling pathway is a fundamental cascade in the innate immune system that mediates the production of pro-inflammatory cytokines, particularly Tumor Necrosis Factor-alpha (TNF-alpha) (PMID: 21151104). This pathway is primarily initiated by the activation of Toll-like receptors (TLRs) or Interleukin-1 receptors (IL-1Rs), which recruit the adapter protein MyD88 (Myeloid differentiation primary response 88) (UniProt: P51617). MyD88 then facilitates the assembly of the 'myddosome' complex, involving IRAK family kinases, which eventually activates the IkappaB kinase (IKK) complex. The IKK complex phosphorylates IkappaB proteins, leading to their degradation and the subsequent release and nuclear translocation of the transcription factor NF-kappaB (UniProt: P19838). Once in the nucleus, NF-kappaB binds to specific promoter regions to drive the expression of TNF-alpha and other inflammatory mediators (PMID: 18583404). Dysregulation of this pathway is linked to chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, as well as certain cancers where it promotes cell survival and proliferation (PMID: 30214317). Therapeutic interventions target various nodes of this pathway, including IRAK4 inhibitors and TNF-alpha antagonists, though systemic inhibition poses risks of significant immunosuppression and opportunistic infections (PMID: 32661310).

Other names

MyD88-dependent TLR signaling pathwayMyD88-NF-kappaB axisTLR-MyD88-NF-kappaB pathwayNF-kappaB / MyD88-dependent TNF-alpha production pathway

The pathway transduces signals from Toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs) through the MyD88 adapter protein to activate the IKK complex, leading to NF-kappaB nuclear translocation and the subsequent transcription of TNF-alpha (PMID: 21151104).