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Event: 1172
Key Event Title
Increased activation, Nuclear factor kappa B (NF-kB)
Short name
Biological Context
Level of Biological Organization |
---|
Cellular |
Cell term
Cell term |
---|
epithelial cell |
Organ term
Organ term |
---|
tissue |
Key Event Components
Process | Object | Action |
---|---|---|
regulation of I-kappaB kinase/NF-kappaB signaling | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
AT1R, lung fibrosis | KeyEvent | Allie Always (send email) | Under development: Not open for comment. Do not cite | Under Development |
TLR9 activation leading to Multi Organ Failure and ARDS | KeyEvent | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | |
Binding to ACE2 leads to lung fibrosis | KeyEvent | Allie Always (send email) | Open for comment. Do not cite | Under Development |
DNA damage and metastatic breast cancer | KeyEvent | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Homo sapiens | Homo sapiens | High | NCBI |
Life Stages
Life stage | Evidence |
---|---|
Not Otherwise Specified | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Mixed | Not Specified |
Key Event Description
The NF-kB pathway consists of a series of events where the transcription factors of the NF-kB family play a key role. The proinflammatory cytokine (IL-1beta) can be activated by NF-kB , including Reactive Oxygen Species produced by NADPH oxidase (NOX). Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. There, this transcription factor can express pro-inflammatory and pro-fibrotic genes. This can be achieved by ROS, IKK enhancer or nuclear translocation enhancer.
How It Is Measured or Detected
NF-kB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010). NF-kB transcription: Lentiviral NF-kB GFP reporter with flow cytometry (Moujalled et al. 2012)
NF-κB translocation: RelA-GFP reporter assay (Wink et al 2017)
IκBa phosphorylation: Western blotting (Miller et al. 2010)
NF-κB p65 (Total/Phospho) ELISA
ELISA for IL-6, IL-8, and Cox
Domain of Applicability
The ROS directly influences NF-κB signalling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999). NIn accordance with the OECD AOP Handbook, the pathway begins with increased levels of reactive oxygen species (ROS), serving as the Molecular Initiating Event (MIE), which subsequently triggers the Activation of the NF-κB Signaling Pathway . This activation, in turn, directly influences the expression of genes involved in the Differential Production of Cytokines and Chemokines , culminating in the regulation of Pro-Inflammatory Responses Transcriptionally Mediated by NF-κB (. The resultant exaggerated and dysregulated pro-inflammatory response contributes to chronic inflammation and tissue damage, representing the Adverse Outcome (AO). This sequence of events is underpinned by the works of McKay and Cidlowski (1999) and aligns with the guidelines set forth in the OECD AOP Handbook.F-κB regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB.
References
McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev. 1999 Aug;20(4):435-59.
Miller SC, Huang R, Sakamuru S, Shukla SJ, Attene-Ramos MS, Shinn P, Van Leer D, Leister W, Austin CP, Xia M. Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action. Biochem Pharmacol. 2010 May 1;79(9):1272-80.
Moujalled DM, Cook WD, Lluis JM, Khan NR, Ahmed AU, Callus BA, Vaux DL. In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it. Cell Death Differ. 2012 May;19(5):808-15.
Wink S, Hiemstra S, Herpers B, van de Water B. High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383.