Nuclear factor kappa B and Signal transducer and activator of transcription 3 signaling pathway components (NF-κB/STAT3)

The NF-κB and STAT3 signaling pathways are central regulators of the innate immune response, particularly in macrophages stimulated by Lipopolysaccharide (LPS) (Liu et al., 2017, PubMed: 28924402). LPS binds to Toll-like receptor 4 (TLR4), triggering a cascade that activates the IκB kinase (IKK) complex, leading to the nuclear translocation of NF-κB transcription factors (primarily p65/p50) and the subsequent expression of pro-inflammatory cytokines such as TNF-α and IL-6 (Oeckinghaus & Ghosh, 2009, PubMed: 19855121). Simultaneously, STAT3 is activated either directly through TLR4-associated kinases or indirectly via autocrine signaling of cytokines like IL-6, which signals through the JAK/STAT pathway (Grivennikov & Karin, 2010, PubMed: 21115689). These two pathways exhibit significant crosstalk, where NF-κB and STAT3 can physically interact or cooperatively bind to promoters of genes involved in inflammation, cell proliferation, and survival (Fan et al., 2013, PubMed: 23543767). Dysregulation of this axis is a hallmark of chronic inflammatory diseases, sepsis, and various cancers, where persistent activation promotes a pro-tumorigenic microenvironment (Yu et al., 2009, PubMed: 19844246). Consequently, components of these pathways, including IKK, JAKs, and the transcription factors themselves, are major targets for anti-inflammatory and anti-neoplastic drug development, with agents like JAK inhibitors and proteasome inhibitors being used to modulate their activity (He & Karin, 2011, PubMed: 21435514).

Other names

NF-kappaB/STAT3 axisTLR4-mediated NF-kB/STAT3 activationLPS-induced inflammatory signaling pathwayNF-kappaB and STAT3 crosstalk

Inhibition of IκB kinase (IKK) activity to prevent NF-κB release, inhibition of Janus kinases (JAK) to prevent STAT3 phosphorylation, direct inhibition of the STAT3 SH2 domain to prevent dimerization, and proteasomal inhibition to prevent the degradation of IκB (He & Karin, 2011, PubMed: 21435514).