The Role of Cell Networks In Response to Diesel Exhaust Particles

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Induction of effective inflammation in the lung in response to environmental and microbial stimuli is dependent upon cooperative signalling between leukocytes and lung tissue cells. The influence of diesel exhaust particles (DEP), on cell networks and its capacity to modulate the inflammatory response to pathogenic stimuli were explored. The effects of DEP SRM 2975 were studied in cocultures of human monocytes and the immortalised bronchial epithelial cell line, BEAS-2B. Cocultures, or monoculture controls, were treated with DEP in the presence or absence of TLR4 and 5 agonists (LPS and flagellin respectively), and IL-1 receptor antagonist. Production of cytokines was explored by western blotting and ELISA; cell signalling was analysed by western blotting. I have described a model in which the production of IL-1 by sentinel cells such as monocytes is key to the activation of tissue cells exposed to endotoxin. Here, I show that this cooperative pathway also facilitates effective responses to flagellin in an IL-1-dependent manner, and enables responses to DEP. More importantly, DEP accentuated the cellular response to minimal amounts of TLR agonists, which in their own right had only modest actions in this coculture system. In addition, in the presence of DEP, the responses induced by endotoxin and flagellin were markedly less amenable to antagonism by the physiological IL-1 antagonist, IL-1ra. This was paralleled with an uncoupling between IL-1 production and release, attributable to DEPs ability to sequester or degrade ATP, a key molecule involved in IL-1 processing and release. These data describe a model of inflammation where DEP amplifies responses to low concentrations of microbial agonists and coupled with its ability to alter ATP levels provides the switch to an IL-1-independent system and alters the nature of the inflammatory milieu induced by TLR agonists.
Original languageEnglish
Publication statusPublished (in print/issue) - Nov 2009


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