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.