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Originally published online as doi:10.1189/jlb.0807533 on December 3, 2007

Published online before print December 3, 2007
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(Journal of Leukocyte Biology. 2008;83:630-639.)
© 2008 by Society for Leukocyte Biology

The IL-4R{alpha} pathway in macrophages and its potential role in silica-induced pulmonary fibrosis

Christopher T. Migliaccio1, Mary C. Buford, Forrest Jessop and Andrij Holian

Center for Environmental Health Sciences, University of Montana, Missoula, Montana, USA

1Correspondence: University of Montana, Center for Environmental Health Sciences, 285C Skaggs Building, Missoula, MT 59812, USA. E-mail: christopher.migliaccio{at}umontana.edu

Crystalline silica exposure can result in pulmonary fibrosis, where the pulmonary macrophage is key as a result of its ability to react to silica particles. In the mouse silicosis model, there is initial Th1-type inflammation, characterized by TNF-{alpha} and IFN-{gamma}. Previous studies determined that Th2 mediators (i.e., IL-13) are vital to development of pulmonary fibrosis. The present study, using in vivo and in vitro techniques, compares silica exposures between Balb/c and Th2-deficient mice in an effort to determine the link between Th2 immunity and silicosis. In long-term experiments, a significant increase in fibrosis and activated interstitial macrophages was observed in Balb/c but not IL-4R{alpha}–/– mice. Additionally, a significant increase in Ym1 mRNA levels, a promoter of Th2 immunity, was determined in the interstitial leukocyte population of silica-exposed Balb/c mice. To elucidate the effects of silica on macrophage function, bone marrow-derived macrophages (BMdM) were exposed to particles and assayed for T cell (TC) stimulation activity. As a control, Ym1 mRNA expression in Balb/c BMdM was determined using IL-4 stimulation. In the in vitro assay, a significant increase in TC activation, as defined by surface markers and cytokines, was observed in the cultures containing the silica-exposed macrophages in wild-type and IL-4R{alpha}–/– mice, with one exception: IL-4R{alpha}–/– BMdM were unable to induce an increase in IL-13. These results suggest that crystalline silica alters cellular functions of macrophages, including activation of TC, and that the increase in Th2 immunity associated with silicosis is via the IL-4R{alpha}-Ym1 pathway.

Key Words: mouse • alternatively activated • T cell • lung






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