Prostaglandin-E2 counteracts interleukin-1β-stimulated upregulation of platelet-derived growth factor α-receptor on rat pulmonary myofibroblasts

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