Am. J. Respir. Cell Mol. Biol., Volume 20, Number 3, March, 1999 433-440

Prostaglandin-E₂ Counteracts Interleukin-1-Stimulated Upregulation of Platelet-Derived Growth Factor -Receptor on Rat Pulmonary Myofibroblasts

James E. Boyle, Pamela M. Lindroos, Annette B. Rice, Limin Zhang, Darryl C. Zeldin, and James C. Bonner

Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park; and Division of Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, North Carolina

The platelet-derived growth factor (PDGF) -receptor (PDGF-R) is upregulated during lung fibrogenesis, and induction of PDGF-R on cultured lung myofibroblasts by interleukin (IL)-1 results in an increased mitogenic response to PDGF. Because IL-1 stimulates prostaglandin (PG) E₂ production, we investigated whether IL-1 could upregulate PDGF-R via a PGE₂-dependent mechanism. IL-1 increased the production of PGE₂ by rat lung myofibroblasts and the cyclooxygenase (COX) inhibitor indomethacin blocked IL-1-induced PGE₂ production. However, indomethacin did not inhibit IL-1-stimulated upregulation of [¹²⁵I]PDGF-AA binding sites, indicating that PDGF-R induction does not require PGE₂ synthesis. Instead, PGE₂ downregulated PDGF-R protein and messenger RNA expression, and counteracted the IL-1-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-R, indicating that endogenous PGE₂ released by IL-1 treatment also contributed to downregulation of PDGF-R. PDGF-R expression was not altered by IL-1 or PGE₂. Pretreatment of myofibroblasts with IL-l 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-1 upregulates both PGE₂ production and PDGF-R expression, these data suggest that PGE₂ functions in a negative feedback loop to limit expression of PDGF-R and suppress PDGF-stimulated myofibroblast proliferation.

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