Key Event Title
|Level of Biological Organization|
Key Event Components
|I-kappaB kinase/NF-kappaB signaling||transcription factor NF-kappa-B subunit||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Glucocorticoid Receptor, Activation||KeyEvent|
|IKK complex inhibition leading to liver injury||KeyEvent|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|All life stages||High|
Key Event Description
The NFkB pathway consists of a series of events where the transcription factors of the NFkB family play the key role. The canonical NFkB pathway can be activated by a range of stimuli, including TNF receptor activation by TNFalpha. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NFkB inhibitor will be K48-linked ubiquitinated and degradated, allowing NFkB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the NFkB pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of NFkB target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors. (Frederiksson 2012). (Gupta et al. 2010).(Huppelschoten 2017).(Liu et al. 2017).
How It Is Measured or Detected
NFkB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010)
NFkB transcription: Lentiviral NFkB GFP reporter with flow cytometry (Moujalled et al. 2012)
NFkB translocation: RelA-GFP reporter assay (Frederiksson 2012) (Huppelschoten 2017)
IkBa phosphorylation: Western blotting (Miller et al. 2010)
Domain of Applicability
The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski 1999; Pernis 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan 2016). Androgen-receptor signalling antagonises transcriptional factors NF-κB(McKay and Cidlowski 1999).
Frederiksson, L., 2012. TNFalpha-signaling in drug induced liver injury. University of Leiden.
Gupta, S.C. et al., 2010. Inhibiting NF-??B activation by small molecules as a therapeutic strategy. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1799(10–12), pp.775–787. Available at: http://dx.doi.org/10.1016/j.bbagrm.2010.05.004.
Huppelschoten, S., 2017. Dynamics of TNFalpha signaling and drug-related liver toxicity. Leiden University.
Liu, T. et al., 2017. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(March), p.17023. Available at: http://www.nature.com/articles/sigtrans201723.
Miller, S.C. et al., 2010. Identification of known drugs that act as inhibitors of NF-κB signaling and their mechanism of action. Biochemical Pharmacology, 79(9), pp.1272–1280. Available at: http://dx.doi.org/10.1016/j.bcp.2009.12.021.
Moujalled, D.M. et al., 2012. In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-?B, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-?B is required to prevent it. Cell Death and Differentiation, 19(5), pp.808–815. Available at: http://dx.doi.org/10.1038/cdd.2011.151.