tion of effective inflammation in the lung in response to environmental and microbial stimuli is dependent on cooperative signaling between leukocytes and lung tissue cells. We explored how these inflammatory networks are modulated by diesel exhaust particles (DEP) using cocultures of human monocytes with epithelial cells. Cocultures, or monoculture controls, were treated with DEP in the presence or absence of LPS or flagellin. Production of cytokines was explored by Western blotting and ELISA; cell signaling was analyzed by Western blotting. Here, we show that responses of epithelial cells to DEP are amplified by the presence of monocytes. DEP amplified the responses of cellular cocultures to very low doses of TLR agonists. In addition, in the presence of DEP, the responses induced by LPS or flagellin were less amenable to antagonism by the physiological IL-1 antagonist, IL-1ra. This was paralleled by the uncoupling of IL-1 production and release from monocytes, potentially attributable to an ability of DEP to sequester or degrade extracellular ATP. These data describe a model of inflammation where DEP amplifies responses to low concentrations of microbial agonists and alters the nature of the inflammatory milieu induced by TLR agonists.cocultures; inflammation; interleukin-1; Toll-like receptors ENVIRONMENTAL EXPOSURE to microbial products through the inhalation of bacterial fragments, such as LPS, has long been associated with exacerbations of airway disease, and levels of LPS within the environment can correlate with severity of asthma (30,38). Asthma and COPD are commonly exacerbated by bacterial and viral infections (3, 24) that can often coexist and synergize with pollutant exposure (8, 46). Inhalation of small particulate matter is also a major cause of airway inflammation, and rising air pollution levels are associated with elevated mortality and increased hospital admissions in individuals with respiratory diseases such as asthma and COPD (2, 10, 45).Diesel exhaust particles (DEP) are the major particulate matter of air pollution and comprise a nanoparticular carbonaceous core, multiple organic components such as polyaromatic hydrocarbons (PAH), transition metals, and adsorbed materials such as pollen and dust. Their small size (5-20 nm; 100-nm aggregates) means that they are often denoted nanoparticles and favors their deposition in the lung (7, 11). Acute and chronic inhalation of DEP in healthy individuals, and those with preexisting respiratory disease, results in respiratory toxicity with consequent development of lung edema, infiltration of polymorphonuclear leukocytes, and the production of proinflammatory cytokines and reactive oxygen species (ROS) (5,36,44,47).The active inflammation that occurs in asthma and COPD leads to the recruitment of monocytes to the alveolar wall (28). Furthermore, urban particulate matter has been shown to cause the release of monocytes from the bone marrow (17, 23). We have previously shown that effective inflammatory responses to bacterial-derived stimuli are media...
