Upstream eventInhibition, IKK complex
Inhibition, Nuclear factor kappa B (NF-kB)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|IKK complex inhibition leading to liver injury||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
Phosphorylated IKK complex will activate the IkBa complex by phosphorylation. For an overview of the phosphorylation sites of NFkB see (Christian, Smith, & Carmody, 2016).The IkBa complex will be K48-ubiquitinated and degraded, allowing NFkB to translocate to the nucleus.
If the IKK complex is inhibited the IkBa complex will not be phosphorylated anymore whereupon the IkBa complex is not degraded and the NFkB complex stays inside the cytoplasm. Therefore no downstream target genes will be transcribed.
Evidence Supporting this KER
The road to discovery of NFkB is described by David Baltimore (Baltimore 2009). Later it became clear that the main event of NFkB activation was IkB phosphorylation. In order the phosphorylate IkB, a kinase was necessary. This turned out to be the IkB kinase, or IKK complex (DiDonato et al. 1997; Karin 1999). Now, it has been well established that IKK complex can activate the NFkB pathway and inhibition leads to NFkB inhibition. This is described in the following reviews:
(Liu et al. 2017)
(Gamble et al. 2012)
(Karin et al. 2004)
(Li & Verma 2002)
(Ghosh & Hayden 2008)
(Hayden & Ghosh 2012)
(Gupta et al. 2010)
Hepatocyte NEMO KO mice stimulated with TNF show no IkBa degradations, inhibition of NFkB and inhibition of target gene transcription (BCL2). (Beraza et al. 2007)
Hepatocyte NEMO KO mice stimulated with TNF related cytokines (TRAIL) are hypersensitive for liver injury (upregulation pJNK and Caspase 3). Protected against Fas-mediated apoptosis (Beraza et al. 2009).
Parenchymal (hepatocyte and endothelial cells) NEMO KO mice show steatohepatitis and hepatocellular carcinoma. TUNEL staining showed increased apoptosis in KO mice (compared to WT and IKK2 KO). NfkB activation induced by LPS is blocked and increased LPS toxicity is observed (Luedde et al. 2007).
Massive liver apoptosis in full NEMO KO mouse embryo’s, lack of NFkB activation after TNF in KO MEFs and sensitized to TNF cytotoxicity (Rudolph et al. 2000).
Specific compound studies:
Flavokawain B (FKB), the hepatotoxic constituent from kava root, induces cell death in HepG2. This is observed with oxidative stress, GSH depletion, IKK activity inhibition and downstream NFkB target inhibition (IkBa). MAPKs were also activated (phosphorylated variants of JNK, p38 and ERK). Addition of GSH rescues cell from death (Zhou et al. 2010).
Uncertainties and Inconsistencies
Few compounds found which inhibit IKK complex and could cause liver injury. Many more compounds which inhibit NFkB pathway and cause liver injury.
Hepatocytes exposed to di-(2-ethylhexyl)phthalate (DEHP) show activation of IKK and NFkB and this lead to hepatic cell death. Cell death is decreased by preexposure to PS-1145, a specific IKK inhibitor (and no Caspase3 activation observed). (Ghosh et al. 2010)
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
Gamble, C. et al., 2012. Inhibitory kappa B kinases as targets for pharmacological regulation. British Journal of Pharmacology, 165(4), pp.802–819.
Karin, M., Yamamoto, Y. & Wang, Q.M., 2004. The IKK NF-κB system: a treasure trove for drug development. Nature Reviews Drug Discovery, 3(1), pp.17–26. Available at: http://www.nature.com/doifinder/10.1038/nrd1279.
Perkins, N.D., 2007. Integrating cell-signalling pathways with NF-??B and IKK function. Nature Reviews Molecular Cell Biology, 8(1), pp.49–62.
Li, Q. & Verma, I.M., 2002. NF-??B regulation in the immune system. Nature Reviews Immunology, 2(10), pp.725–734.
Ghosh, S. & Hayden, M.S., 2008. New regulators of NF-kB in inflammation. Nature Reviews Immunology, 8(11), pp.837–848.
Hayden, M.S. & Ghosh, S., 2012. NF-kB, the first quarter-century: remarkable progress and outstanding questions. , pp.203–234.
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.