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|
|IL-1 receptor antagonist（IL-1Ra）(Anakinra)|
|anti-IL-1b antibody (Canakinumab)|
|soluble IL-1R (Rilonacept)|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|All life stages||High|
Key Event Description
The NF-kB pathway consists of a series of events where the transcription factors of the NF-kB family play the key role. The NF-kB pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a, or IL-1R1 activation by IL-1a or b. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This NF-kB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-kB to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. (Frederiksson 2012). (Gupta et al. 2010).(Huppelschoten 2017).(Liu et al. 2017). Therefore, inhibition of IL-1R1 activation suppresses activation of NF-κB.
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 (Frederiksson 2012) (Huppelschoten 2017)
IκB 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 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 signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999).
Evidence for Perturbation by Stressor
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.
Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.
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.
McKay, L.I., Cidlowski, J.A., 1999. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20, 435-459.
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.
Pernis, A.B., 2007. Estrogen and CD4+ T cells. Curr Opin Rheumatol 19, 414-420.
Straub, R.H., 2007. The complex role of estrogens in inflammation. Endocr Rev 28, 521-574.