NF-κB Signaling Pathway

Canonical source: hsa04064

Pathway Overview

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a master regulator of inflammatory gene expression, governing immune responses, cell survival, and proliferation. The pathway exists in canonical and non-canonical forms. The canonical pathway is triggered by pro-inflammatory stimuli (TNF, IL-1, LPS, viral RNA): IκB kinase (IKK) phosphorylates IκBα, leading to its ubiquitination and proteasomal degradation, which releases NF-κB dimers (e.g., RelA/p65–p50) for nuclear translocation and target gene activation. Key targets include IL6, IL8, TNF, IL33, COX-2, and adhesion molecules. Environmental pollutants such as PM2.5 activate NF-κB via reactive oxygen species (ROS)–mediated IKK activation; particulate matter downregulates microRNAs that suppress IKK-β. Tissue-specific activity in bronchial epithelium, macrophages, and endothelium underlies respiratory and cardiovascular disease pathogenesis.

Environmental Triggers

Exposure	Trigger type
air-pollution	ROS-mediated IKK activation
tobacco-smoke-prenatal	Oxidative stress and direct activation of IKK
endotoxin	TLR4–MyD88 signaling activates IKK complex

Genetic Modulation Points

Key genes

il33— Upstream alarmin; induced by NF-κB

Tissue Specificity

bronchial epithelium— Primary site of PM2.5-induced NF-κB activation; IL33, IL8 upregulation

macrophages— Classical inflammatory response; cytokine production

endothelium— Adhesion molecule expression; vascular inflammation

Disease Relevance

Linked diseases

asthma— Core inflammatory driver; IL33 induction

Linked exposures

air-pollution— PM2.5 activates NF-κB via ROS; induces IL33 and cytokine cascade

Pathway Diagram

Diagram asset: /diagrams/nfkb-pathway.svg

Evidence Nodes

Evidence for this pathway is derived from:

3 environmental trigger(s)
1 key gene(s)
1 linked disease(s)
1 linked exposure(s)

References

1.Li R, et al. (2017). Exposure to PM2.5 induces aberrant activation of NF-κB in human airway epithelial cells by downregulating miR-331 expression. Environmental Toxicology and Pharmacology. doi:10.1016/j.etap.2017.02.011
2.Hayden MS, Ghosh S (2004). NF-κB and the immune response. Oncogene. doi:10.1038/sj.onc.1207457
3.Kanehisa M, et al. (2023). KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research. doi:10.1093/nar/gkac963
4.Razani-Boroujerdi S, et al. (2020). Particulate matter induces inflammatory cytokine production via activation of NFκB by TLR5-bearing B cells in lung cancer. Proceedings of the National Academy of Sciences. doi:10.1073/pnas.1906806117
5.Risom L, et al. (2003). Regulation of COX-2 Expression and IL-6 Release by Particulate Matter in Airway Epithelial Cells. American Journal of Physiology. doi:10.1152/ajplung.00109.2003