Prostaglandin-E2 counteracts interleukin-1beta-stimulated upregulation of platelet-derived growth factor alpha-receptor on rat pulmonary myofibroblasts.
The platelet-derived growth factor (PDGF) alpha-receptor (PDGF-Ralpha) is upregulated during lung fibrogenesis, and induction of PDGF-Ralpha on cultured lung myofibroblasts by interleukin (IL)-1beta results in an increased mitogenic response to PDGF. Because IL-1beta stimulates prostaglandin (PG) E2 production, we investigated whether IL-1beta could upregulate PDGF-Ralpha via a PGE2-dependent mechanism. IL-1beta increased the production of PGE2 by rat lung myofibroblasts and the cyclooxygenase (COX) inhibitor indomethacin blocked IL-1beta-induced PGE2 production. However, indomethacin did not inhibit IL-1beta-stimulated upregulation of [125I]PDGF-AA binding sites, indicating that PDGF-Ralpha induction does not require PGE2 synthesis. Instead, PGE2 downregulated PDGF-Ralpha protein and messenger RNA expression, and counteracted the IL-1beta-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-Ralpha, indicating that endogenous PGE2 released by IL-1beta treatment also contributed to downregulation of PDGF-Ralpha. PDGF-Rbeta expression was not altered by IL-1beta or PGE2. Pretreatment of myofibroblasts with IL-lbeta 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 approximately 50%. Because IL-1beta upregulates both PGE2 production and PDGF-Ralpha expression, these data suggest that PGE2 functions in a negative feedback loop to limit expression of PDGF-Ralpha and suppress PDGF-stimulated myofibroblast proliferation.
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
J E
JE
Boyle
P M
PM
Lindroos
A B
AB
Rice
L
L
Zhang
D C
DC
Zeldin
J C
JC
Bonner
D000818:Animals; D000970:Antineoplastic Agents; D015232:Dinoprostone / Q000494:pharmacology*; D004336:Drug Antagonism; D005347:Fibroblasts; D007375:Interleukin-1 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008934:Mitogens; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D000970:Antineoplastic Agents; D007375:Interleukin-1; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor; D015232:Dinoprostone