Role of urokinase in the activation of macrophage-associated TGF-beta in silica-induced lung fibrosis.
Since tumor growth factor beta (TGF-beta) and its receptor are ubiquitously expressed and because latent TGF-beta cannot bind to the cell surface receptor, the ability of a cell to activate latent TGF-beta upon secretion represents an important regulatory mechanism of TGF-beta action. In vivo, the protease plasmin is considered to be one of the main enzymes operative in the proteolytic cleavage of the latency-associated peptide moiety from TGF-beta, which converts it into the biologically active form. The TGF-beta response was characterized in alveolar macrophages during pulmonary inflammation (d 3) and fibrosis (d 120) induced by a single intratracheal instillation of silica particles (5 mg/mouse). To appreciate the role of urokinase-type plasminogen activator (uPA) in the activation of TGF-beta, the production of total, active and latent TGF-beta by explanted alveolar macrophages was compared in uPA-deficient (uPA-/-) mice and their normal counterparts (uPA+/+). At d 3 and 120 after silica treatment, a significant increase in cell-associated PA activity was found in uPA+/+ mice compared to that of saline controls. As expected, this response was almost totally absent in uPA-/- mice. Alveolar macrophages from uPA+/+ controls were found to release TGF-beta mainly expressed in a biologically active form. In response to silica treatment, inflammatory cells were found to upregulate, especially at the fibrotic stage, their secretion of total and bioactive TGF-beta. No significant difference was found between uPA-/- and uPA+/+ silica-treated animals for the expression of total, active, or latent TGF-beta. Although it has previously been reported that macrophage surface activation of TGF-beta is dependent on both plasmin generation and uPA cell surface receptor, no evidence was found to support this hypothesis in the present study.
Matrat
M
M
Industrial Toxicology and Occupational Medicine Unit, Catholic University of Louvain, Brussels, Belgium.
Lardot
C
C
Huaux
F
F
Broeckaert
F
F
Lison
D
D
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D005260:Female; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D012822:Silicon Dioxide; D010959:Tissue Plasminogen Activator / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology
D015415:Biomarkers; D016212:Transforming Growth Factor beta; D012822:Silicon Dioxide; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator