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Calcium and ROS-mediated activation of transcription factors and TNF- cytokine gene expression in macrophages exposed to ultrafine particles

¹School of Life Sciences, Napier University, and ⁴ELEGI Laboratory, University of Edinburgh, Edinburgh, United Kingdom; ²Particle Research Core, Institut für Umweltmedizinische Forschung, Düsseldorf, Germany; and ³Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, North Carolina

Submitted 5 May 2003 ; accepted in final form 1 October 2003

Ultrafine (Uf) particles are a component of particulate air pollution suggested to be responsible for the health effects associated with elevations of this pollutant. We have previously suggested that Uf particles, through the induction of oxidative stress, may induce inflammation in the lung, thus exacerbating preexisting illness in susceptible individuals. Alveolar macrophages are considered to play a key role in particlemediated inflammation and lung disease. The effect of Uf particles on rat alveolar macrophages and human blood monocytes was investigated with reference to the roles of calcium and reactive oxygen species (ROS). TNF- protein release, intracellular calcium concentration, TNF- mRNA expression, and transcription factor activation were studied as end points after treatment of rat alveolar macrophages or peripheral blood monocytes. The calcium channel blocker verapamil, the intracellular calcium chelator BAPTA-AM, the calmodulin inhibitor W-7, and the antioxidants Trolox and Nacystelin (NAL) were included in combination with Uf particles. Verapamil reduced intracellular calcium concentration in rat alveolar macrophages on stimulation with Uf particles. This effect was also apparent with transcription factor AP-1 activation. All antagonists and antioxidants reduced Uf-stimulated nuclear localization of the p50 and p65 subunits of NF-B in human monocytes. Verapamil, BAPTA-AM, and NAL reduced Uf-stimulated TNF- protein release, whereas only verapamil reduced Uf-stimulated mRNA expression in rat alveolar macrophages. In human monocytes, verapamil, Trolox, BAPTA-AM, and W-7 reduced Uf-stimulated TNF- protein release. These findings suggest that Uf particles may exert proinflammatory effects by modulating intracellular calcium concentrations, activation of transcription factors, and cytokine production through a ROS-mediated mechanism.

reactive oxygen species; tumor necrosis factor-

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