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|
|Pralnacasan (VX-740) and Belnacasan (VX-765)|
|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 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
Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent. Again, age-dependent difference in IL-1 signaling is not known.
The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).
These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.
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.
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.