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Relationship: 1828

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition, Nuclear factor kappa B (NF-kB) leads to Activation, Caspase 8 pathway

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
IKK complex inhibition leading to liver injury adjacent Moderate Moderate Nanette Vrijenhoek (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

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.