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.