Upstream eventResponse, Keratinocytes
Activation, Dendritic Cells
Key Event Relationship Overview
AOPs Referencing Relationship
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Life Stage Applicability
How Does This Key Event Relationship Work
Biochemical or intracellular pathways affected by the action of reactive chemicals on molecular targets are incompletely known. However, there is evidence that during the sensitisation response, haptenprotein conjugates (hereafter noted as haptens) can react with cell surface proteins and activate mitogenactivated protein kinase signalling pathways. In particular, the biochemical pathways involving extracellular signal-regulating kinases- the c-Jun N-terminal kinases and the p38 kinases have been shown to be activated upon exposure to protein-binding chemicals. These pathways are of particular importance in keratinocytes and dendritic cell response to skin sensitizers.
Uptake of the hapten by keratinocytes activates multiple events, including the release of pro-inflammatory cytokines and the induction of cyto-protective cellular pathways. Activation of the pro-inflammatory cytokine IL-18 results from cleavage of inactive IL-18 precursor protein by inflammasome-associated caspase-1. Sensitizers can activate the inflammasome (;) and in so doing induce IL-18 production. Intracellular Nodlike receptors (NLR) contain sensors for a number of cellular insults. Upon activation (by a currently unknown mechanism), NLRs oligomerise form molecular complexes (i.e. inflammasomes) that are involved in the activation of inflammatory-associated caspases, including caspase-1. Inductions of intracellular levels of IL-18 exhibit responses upon exposure to sensitizers which can be used to establish potency.
Under the influence of fibroblast- blood endothelial- and lymph endothelial-chemokines (e.g. CCL19, CCL21) and epidermal cytokines (e.g. interleukin (IL), IL-1 α, IL-1β, IL-18, tumour necrosis factor alpha (TNF-α)) maturing dendritic cells migrate from the epidermis to the dermis of the skin and then to the proximal lymph nodes, where they can present the hapten-protein complex to T-cells via a major histocompatibility complex molecule (; ).
Weight of Evidence
Empirical Support for Linkage
Include consideration of temporal concordance here
Uncertainties or Inconsistencies
Uncertainties include the significance of Th1 or type 1 (IFN-γ) versus Th2 or type 2 (IL-2, IL-4, IL-13) cytokine secretion profiles ), and sensitisation measurements in different in vivo models. - Inconsistencies within the reported data are seen. There are differences between in vitro responses for highly similar chemicals (see ;). There are differences within and between in vivo test results for highly similar chemicals (see Annex C of the European Centre for Ecotoxicological and Toxicological Chemicals, 2010). Highly hydrophobic chemicals, which are in vivo sensitizers, are not active in aquatic-based in chemico or in vitro assays. The specific nature of the relationship between irritation and sensitisation has yet to be elucidated.
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
Evidence Supporting Taxonomic Applicability
While in vivo testing focuses on selected mammals including man, the key events for this AOP appear to be conserved across mammals.
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