Elucidating the cell signalling events that activate nanomaterial induced inflammation using pharmacological inhibitors.

Nanomaterials (NMs) are defined as having at least one dimension that is 1-100nm in diameter. Existing studies have demonstrated that NMs can activate inflammatory responses in the lungs. However, the cellular signalling pathway that mediates the up regulation of pro-inflammatory cytokines in response to NM exposure has not been fully investigated. Epidemiology and laboratory studies have established that the ultrafine component of particulate air pollution, which is similar in size to NMs, causes adverse health impacts that are mediated by an increase in reactive oxygen species (ROS) generation and up-regulation of pro-inflammatory cytokines (such as interleukin (IL)-8 via activation of the transcription factor NF-κB. NF-κB is a protein that stimulates the expression of pro-inflammatory genes, when inactive it is found in the cytoplasm and when active it translocates to the nucleus. It is hypothesised that NMs may also cause toxicity via activation of NF-κB signalling. A variety of approaches can be used to investigate the involvement of NF-κB signalling in the cellular response to NMs such as the use of immunostaining (to visualise the location of NF-κB in the cell), and the use of pharmacological inhibitors which target different parts of the NF-κB signalling cascade. To investigate the role of NF-κB in NM induced pro-inflammatory signalling in Calu-3 lung cells and J774 macrophages, 24-hour co-exposures of NMs and pharmacological inhibitors that have different target sites in the NF-κB signalling pathway were performed and the impact on pro-inflammatory cytokine production was assessed.