The IL-4Ralpha pathway in macrophages and its potential role in silica-induced pulmonary fibrosis.
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-4Ralpha(-/-) 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-4Ralpha(-/-) mice, with one exception: IL-4Ralpha(-/-) 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-4Ralpha-Ym1 pathway.
Center for Environmental Health Sciences, University of Montana, Missoula, MT 59812, USA. christopher.migliaccio@umontana.edu
Christopher T
CT
Migliaccio
Mary C
MC
Buford
Forrest
F
Jessop
Andrij
A
Holian
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D002455:Cell Division; D003094:Collagen / Q000032:analysis; D005434:Flow Cytometry; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012822:Silicon Dioxide / Q000633:toxicity*; D013601:T-Lymphocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D053662:Interleukin-4 Receptor alpha Subunit
D003094:Collagen; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012822:Silicon Dioxide; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit