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Ozone Exposure of Macrophages Induces an Alveolar Epithelial Chemokine Response through IL-1

¹ Department of Medicine, National Jewish Medical and Research Center, Denver; and ² Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Robert J. Mason, M.D., Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: masonb{at}njc.org

Ozone is known to produce an acute influx of neutrophils, and alveolar epithelial cells can secrete chemokines and modulate inflammatory processes. However, direct exposure of alveolar epithelial cells and macrophages to ozone (O₃) produces little chemokine response. To determine if cell–cell interactions might be responsible, we investigated the effect of alveolar macrophage–conditioned media after ozone exposure (MO₃CM) on alveolar epithelial cell chemokine production. Serum-free media were conditioned by exposing a rat alveolar macrophage cell line NR8383 to ozone for 1 hour. Ozone stimulated secretion of IL-1, IL-1β, and IL-18 from NR8383 cells, but there was no secretion of chemokines or TNF-. Freshly isolated type II cells were cultured, so as to express the biological markers of type I cells, and these cells are referred to as type I–like cells. Type I–like cells were exposed to diluted MO₃CM for 24 hours, and this conditioned medium stimulated secretion of cytokine-induced neutrophil chemattractant-1 (CXCL1) and monocyte chemoattractant protein-1 (CCL2). Secretion of these chemokines was inhibited by the IL-1 receptor antagonist. Although both recombinant IL-1 and IL-1β stimulated alveolar epithelial cells to secrete chemokines, recombinant IL-1 was 100-fold more potent than IL-1β. Furthermore, neutralizing anti-rat IL-1 antibodies inhibited the secretion of chemokines by alveolar epithelial cells, whereas neutralizing anti-rat IL-1β antibodies had no effect. These observations indicate that secretion of IL-1 from macrophages stimulates alveolar epithelial cells to secrete chemokines that can elicit an inflammatory response.

Key Words: alveolar epithelial cells • cytokine-induced neutrophil chemoattractant • monocyte chemoattractant protein-1 • IL-1 • cell–cell interactions

CLINICAL RELEVANCE The acute inflammatory response produced by ozone is likely due to cell–cell interactions, whereby one cell signals another to secrete chemokines. The clinical implication is that the inflammatory response could be blocked by interrupting this paracrine signaling with drugs like IL-1 antagonists.