Toxicity of keratinocytes, the major cell type in the epidermis, is found in several skin inflammatory diseases. Environmental influences such as chemicals, UV light, mechanical insult, or extreme temperatures can cause necrosis of keratinocytes leading to failure of local homeostasis, breaching of the skin barrier, and the potential for infection. In such situations dermal dendritic cells (DCs) may be the important sentinels by responding to danger signals released by the dying cells and potentially activating the adaptive immune system. The aim of this project is the development of a human two cell model to study the influence of skin sensitisers and irritants on DCs in the presence of keratinocytes and test the hypothesis that DCs can respond directly to keratinocyte damage via the release of Interleukin-1 alpha (IL-1α) from the dying cells. The coculture of sensitiser/irritant treated HaCaT cells with human monocytederived DCs led to activation (upregulation of cell surface markers and cytokine/chemokine production), and an increase in T cell stimulatory activity for the sensitisers and the irritants. The supernatant produced by sensitiser and irritant-labelled HaCaT cells was sufficient to induce DC maturation, again showing no difference between sensitisers and irritants. Both HaCaT cells and primary keratinocytes (EpiDermTM) released IL-1α after chemical exposure. IL-1α neutralising antibodies attenuated DC maturation induced by chemical-treated HaCaT supernatants. Furthermore the effect of IL-1α on DCs was studied. Our in vitro model studying the interaction between keratinocytes and DCs suggests that both sensitisers and irritants can lead to cell damage in the skin which is associated with the release of IL-1α and possibly other danger signals. These can activate DCs in the underlying dermis and lead to activation of the adaptive immune system causing the clearance of infections or resulting in allergic reactions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:565879 |
| Date | January 2012 |
| Creators | Matjeka, I. T. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1346472/ |
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