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AOP: 278
Title
IKK complex inhibition leading to liver injury
Short name
Graphical Representation
Point of Contact
Contributors
- Nanette Vrijenhoek
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on April 29, 2023 16:03
Revision dates for related pages
Page | Revision Date/Time |
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Inhibition, IKK complex | January 07, 2019 10:54 |
Inhibition, Nuclear factor kappa B (NF-kB) | March 02, 2023 01:58 |
Activation, Caspase 8 pathway | March 07, 2019 04:16 |
Increase, Cell injury/death | May 27, 2024 07:23 |
Activation, Tissue resident cells (Kuppfer cells) | January 07, 2019 09:04 |
Necrotic Tissue | March 07, 2019 04:19 |
Liver Injury | March 07, 2019 04:23 |
Increase, proinflammatory mediators (TNFalpha) | January 07, 2019 10:44 |
Inhibition, IKK complex leads to Inhibition, Nuclear factor kappa B (NF-kB) | March 07, 2019 05:52 |
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 | March 07, 2019 05:56 |
Activation, Caspase 8 pathway leads to Cell injury/death | March 07, 2019 06:03 |
Cell injury/death leads to Necrotic Tissue | March 07, 2019 06:05 |
Necrotic Tissue leads to Liver Injury | March 07, 2019 06:07 |
Activation, Tissue resident cells (Kuppfer cells) leads to Increase, proinflammatory mediators (TNFalpha) | January 07, 2019 10:48 |
Abstract
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 1574 | Inhibition, IKK complex | Inhibition, IKK complex |
KE | 202 | Inhibition, Nuclear factor kappa B (NF-kB) | Inhibition, Nuclear factor kappa B (NF-kB) |
KE | 1575 | Activation, Caspase 8 pathway | Activation, Caspase 8 pathway |
KE | 55 | Increase, Cell injury/death | Cell injury/death |
KE | 1576 | Activation, Tissue resident cells (Kuppfer cells) | Activation, Tissue resident cells (Kuppfer cells) |
KE | 1579 | Increase, proinflammatory mediators (TNFalpha) | Increase, proinflammatory mediators (TNFalpha) |
AO | 1548 | Necrotic Tissue | Necrotic Tissue |
AO | 1549 | Liver Injury | Liver Injury |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
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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 Cell injury/death | adjacent | High | High |
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 |
Cell injury/death leads to Activation, Tissue resident cells (Kuppfer cells) | non-adjacent | Moderate | Moderate |