API

Relationship: 834

Title

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Activation, Keratinocytes leads to Activation, Dendritic Cells

Upstream event

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Activation, Keratinocytes

Downstream event

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Activation, Dendritic Cells

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
Covalent Protein binding leading to Skin Sensitisation directly leads to Moderate

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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Uptake of the hapten by keratinocytes activates multiple events, including the release of pro-inflammatory cytokines (e.g. IL-18) and the induction of cyto-protective cellular pathways. 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 ([1];[2]).

This KER description is based only on the OECD document 2012 and needs updating.

Weight of Evidence

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Biological Plausibility

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Keratinocyte response activates multiple events, including the release of pro-inflammatory cytokines (e.g. IL-18) and the induction of cyto-protective cellular pathways. Under the influence of fibroblast- blood endothelial- and lymph endothelial-chemokines (e.g. CCL19, CCL21) and epidermal cytokines (e.g. 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[1];[2].

Empirical Support for Linkage

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Matjeka et al. (2012) exposed HaCaT cell line used as a model of human keratinocytes to skin sensitisers for one hour and then, after washed off, cocultured them with dendritic cells. Data showed that exposure of dendritic cells to chemically treated HaCaT cells led to the activation of dendritic cells measured by CD83 and CD86 upregulation[3].

Uncertainties or Inconsistencies

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Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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References

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  1. 1.0 1.1 Antonopoulos C, Cumberbatch M, Mee JB, Dearman RJ, Wei XQ, Liew FY, Kimber I, Groves RW. 2008. IL-18 is a key proximal mediator of contact hypersensitivity and allergen induced Langerhans cell migration in murine epidermis. J. Leukoc. Biol. 83: 361-367.
  2. 2.0 2.1 Ouwehand K, Santegoets SJAM, Bruynzeel DP, Scheper RJ, de Gruijl TD, Gibbs S. 2008. CXCL12 is essential for migration of activated Langerhans cells for epidermis to dermis. Eur. J. Immunol. 38: 3050-3059.
  3. Matjeka T, Summerfield V, Noursadeghi M, Chain BM. 2012. Chemical toxicity to keratinocytes triggers dendritic cell activation via an IL-1 path. J. Allergy Clin. Immunol. Letters to the editor:247-205.