|| Checking for direct PDF access through Ovid
The platelet-derived growth factor (PDGF) α-receptor (PDGF-Rα) is upregulated during lung fibrogenesis, and induction of PDGF-Rα on cultured lung myofibroblasts by interleukin (IL)-1β results in an increased mitogenic response to PDGF. Because IL-1β stimulates prostaglandin (PG) E2 production, we investigated whether IL-1β could upregulate PDGF-Rα via a PGE2-dependent mechanism. IL-1β increased the production of PGE2 by rat lung myofibroblasts and the cyclooxygenase (COX) inhibitor indomethacin blocked IL-1β-induced PGE2 production. However, indomethacin did not inhibit IL-1β-stimulated upregulation of [125I]PDGF-AA binding sites, indicating that PDGF-Rα induction does not require PGE2 synthesis. Instead, PGE2 downregulated PDGF-Rα protein and messenger RNA expression, and counteracted the IL-1β-stimulated increase in [125I]PDGF-AA binding. Pretreatment of cells with indomethacin or the COX-2 specific inhibitor NS-398 attenuated the suppressive effect of exogenous PGE2 on PDGF-Rα, indicating that endogenous PGE2 released by IL-1β treatment also contributed to downregulation of PDGF-Rα. PDGF-Rβ expression was not altered by IL-1β or PGE2. Pretreatment of myofibroblasts with IL-lβ increased PDGF-stimulated mitogenesis, and this effect was blocked by coincubation with PGE2. In contrast, PGE2 enhanced epidermal growth factor- or basic fibroblast growth factor-2-stimulated cell proliferation ∼ 50%. Because IL-1β upregulates both PGE2 production and PDGF-Rα expression, these data suggest that PGE2 functions in a negative feedback loop to limit expression of PDGF-Rα and suppress PDGF-stimulated myofibroblast proliferation.