Upstream eventInhibition, Nuclear factor kappa B (NF-kB)
Activation, Caspase 8 pathway
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|IKK complex inhibition leading to liver injury||adjacent||Moderate||Moderate|
Life Stage Applicability
Key Event Relationship Description
The downstream targets of NFkB are genes involved in cell survival and proliferation. When NFkB is inhibited, less of these cell survival genes will be transcribed, making the cell more susceptible for cell death pathways, like the caspase 8 pathway. (Frederiksson, 2012).In other words, lack of NFkB inhibition will lead to no inhibition of the capase pathway.
Evidence Supporting this KER
It has been well established that NFkB inhibits apoptosis. This is shown in the following reviews:
(Oeckinghaus et al. 2011) RIP1 dependent signaling pathways
(Kruidering & Evan 2000) Mechanisms of caspase 8
(Brenner et al. 2015) TNF induced necroptosis via procaspase8 and RIPK1
(Hayden & Ghosh 2012) Extensive review NFkB
Experiments supporting the plausibility
TNF induced NFkB activation is not impaired in caspases 8 deficient (or FLIP deficient) MEFs, but caspase 8 is required for TNF to cause cell death. (Moujalled et al. 2012)
Griseofulvin: Inhibit NFkB signaling in combination with TNF measured by ICAM1 reduction in HepG2. Also shows synergistic cell death with TNF. Knockdown of Caspase8 rescued the cell from apoptosis (Huppelschoten 2017).
Diclofenac: Inhibit NFkB signaling in combination with TNF measured by ICAM1 reduction in HepG2. Also shows synergistic cell death with TNF. Knockdown of Caspase8 rescued the cell from apoptosis (Huppelschoten 2017).
Valproic acid: Synergistic cell death with TNF, rescues upon caspase8 knockdown in HepG2. VPA inhibit Nfkb-pathway in HepG2? [Testing planned].
Uncertainties and Inconsistencies
Caspase 8 activation leads to cell death but this is blocked in healthy cells by NFkB (Murphy 2012).
The balance between NfkB activation and cell death is complicated and includes crosstalk between several pathways. For example, not only target genes of NFkB signaling can induce survival, but also RIPK1 signaling with pro caspase8 block necrosis. (Brenner et al. 2015)
(Dondelinger et al. 2015) IKK subunits alpha and beta phosphorylate RIPK1, thereby inducing apoptosis via FADD/caspase-8: IKK inactivation induces cell death via RIPK1. NFkB is indeed inhibited and induces cell death, however, in parallel, RIPK1 dependent cell death is quicker. This pathway is also activated by IKK complex inactivation.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Oeckinghaus, A., Hayden, M.S. & Ghosh, S., 2011. Crosstalk in NF-κB signaling pathways. Nature Immunology, 12(8), pp.695–708. Available at: http://www.nature.com/doifinder/10.1038/ni.2065.
Kruidering, M. & Evan, G., 2000. Caspase-8 in Apoptosis: The Beginning of “The End”? IUBMB Life, 50(2), pp.85–90. Available at: http://doi.wiley.com/10.1080/713803693.
Brenner, D., Blaser, H. & Mak, T.W., 2015. Regulation of tumour necrosis factor signalling: Live or let die. Nature Reviews Immunology, 15(6), pp.362–374. Available at: http://dx.doi.org/10.1038/nri3834.
Hayden, M.S. & Ghosh, S., 2012. NF-kB, the first quarter-century: remarkable progress and outstanding questions. , pp.203–234.
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.
Huppelschoten, S., 2017. Dynamics of TNFalpha signaling and drug-related liver toxicity. Leiden University.
Murphy, K., 2012. Jayneway’s Immunology 8th ed.,
Dondelinger, Y. et al., 2015. NF-κB-Independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-Dependent Apoptotic and Necroptotic Cell Death during TNF Signaling. Molecular Cell, 60(1), pp.63–76.