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Aop: 278

AOP Title

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IKK complex inhibition leading to liver injury

Short name:

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IKK complex inhibition leading to liver injury

Graphical Representation

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Authors

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Vrijenhoek, N.G. 1

1Leiden Academic Center for Drug Research, Leiden Univeristy, Leiden, The Netherlands

Point of Contact

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Nanette Vrijenhoek   (email point of contact)

Contributors

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  • Nanette Vrijenhoek

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on January 07, 2019 10:48

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Revision dates for related pages

Page Revision Date/Time
Inhibition, IKK complex January 07, 2019 10:54
Inhibition, Nuclear factor kappa B (NF-kB) September 16, 2017 10:14
Activation, Caspase 8 pathway January 07, 2019 08:48
N/A, Cell injury/death December 05, 2018 08:26
Activation, Tissue resident cells (Kuppfer cells) January 07, 2019 09:04
Necrotic Tissue December 19, 2018 09:40
Liver Injury December 19, 2018 09:40
Increase, proinflammatory mediators (TNFalpha) January 07, 2019 10:44
Inhibition, IKK complex leads to Inhibition, Nuclear factor kappa B (NF-kB) January 07, 2019 09:10
N/A, Cell injury/death leads to Activation, Tissue resident cells (Kuppfer cells) January 07, 2019 09:14
Inhibition, Nuclear factor kappa B (NF-kB) leads to Activation, Caspase 8 pathway January 07, 2019 09:11
Activation, Caspase 8 pathway leads to N/A, Cell injury/death January 07, 2019 09:11
N/A, Cell injury/death leads to Necrotic Tissue January 07, 2019 09:12
Necrotic Tissue leads to Liver Injury December 19, 2018 09:45
Activation, Tissue resident cells (Kuppfer cells) leads to Increase, proinflammatory mediators (TNFalpha) January 07, 2019 10:48

Abstract

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Inflammation has a critical role in liver and other types of injury. Activation of inflammatory events leads to the release of several cytokines, including TNFalpha. When this proinflammatory cytokine is released it can stimulate the TNF-receptor (TNFR), leading to a cascade of pathway activations. However, chemicals can alter these pathways in several ways and influence the TNFR related cascades.

This AOP describes the key events of chemically induced IKK complex inhibition which leads to liver injury during TNF signaling. This AOP starts with the molecular initiating event  “inhibition of the IKK complex”. When the IKK complex is inhibited, the NFkB pathway activation is disturbed, leading to less transcription of anti-apoptotic genes. Then, without apoptosis protection, the activation of Caspase 8, is not inhibited anymore. Caspase 8 activates caspase 3, leading to apoptosis, or cell death. Finally, too much cell death will lead to necrotic tissue and eventually liver failure.

This AOP will collect information about NFkB signaling and will contribute to the mechanistic insights of the inflammatory pathways during hepatotoxicity. Furthermore, since inflammation is a reoccurring KE in several AOPs, this AOP will expand the knowledge of current AOPs of the influence of TNF signaling and compound induced toxicity.

 


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1574 Inhibition, IKK complex Inhibition, IKK complex
2 KE 202 Inhibition, Nuclear factor kappa B (NF-kB) Inhibition, Nuclear factor kappa B (NF-kB)
3 KE 1575 Activation, Caspase 8 pathway Activation, Caspase 8 pathway
4 KE 55 N/A, Cell injury/death N/A, Cell injury/death
5 KE 1576 Activation, Tissue resident cells (Kuppfer cells) Activation, Tissue resident cells (Kuppfer cells)
6 KE 1579 Increase, proinflammatory mediators (TNFalpha) Increase, proinflammatory mediators (TNFalpha)
7 AO 1548 Necrotic Tissue Necrotic Tissue
8 AO 1549 Liver Injury Liver Injury

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition, IKK complex leads to Inhibition, Nuclear factor kappa B (NF-kB) adjacent High High
Inhibition, Nuclear factor kappa B (NF-kB) leads to Activation, Caspase 8 pathway adjacent Moderate Moderate
Activation, Caspase 8 pathway leads to N/A, Cell injury/death adjacent High High
N/A, Cell injury/death leads to Necrotic Tissue adjacent High High
Necrotic Tissue leads to Liver Injury adjacent High High
Activation, Tissue resident cells (Kuppfer cells) leads to Increase, proinflammatory mediators (TNFalpha) adjacent High High
N/A, Cell injury/death leads to Activation, Tissue resident cells (Kuppfer cells) non-adjacent Moderate Moderate

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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