IL-1 DOWN-REGULATES PLATELET-DERIVED GROWTH-FACTOR-ALPHA RECEPTOR GENE-EXPRESSION AT THE TRANSCRIPTIONAL LEVEL IN HUMAN OSTEOBLASTIC CELLS

Regulation of the platelet-derived growth factor (PDCF)-alpha receptor is thought to play an important role in pathophysiologic processes. P reviously, we have reported that IL-1 has the potential to regulate PD GF-induced biologic activity in both normal human osteoblastic cells a nd the human osteoblastic cell line, MG-63, by decreasing the expressi on of PDGF-alpha receptor mRNA. In the present studies, we analyzed th e effects of IL-1 on transcription rates and the stability of PDGF-alp ha receptor mRNA in MC-63 cells. The data indicate that the t(1/2) of PDGF-alpha receptor mRNA is approximately 3.3 h after incubation with the RNA II polymerase transcription inhibitor 5,6-dichloro-1 beta-D-ri bofuranosylbenzimidazole (DRB). Approximately the same t(1/2) (3.1 h) was obtained when osteoblastic cells were incubated with IL-1. The t(1 /2) for PDGF-alpha receptor mRNA for cells incubated with both IL-1 an d DRB was 3 h. This finding suggests that the levels of PDGF-alpha rec eptor mRNA transcripts are not regulated by posttranscriptional mechan isms. Results of nuclear run-on analysis were consistent with this con clusion, demonstrating that IL-1 modulates PDGF-alpha receptor gene ex pression at the transcriptional level. Surprisingly, incubation of cel ls with cycloheximide also caused down-regulation of PDGF-alpha recept or mRNA, which suggests that synthesis of a labile factor is necessary for constitutive expression. The functional consequence of down-regul ation of PDGF-alpha receptors by IL-1 was also assessed. By using chem otaxis assays, we demonstrated that IL-1 significantly inhibited PDGF- AA-mediated migration in human MG-63 osteoblastic sarcoma cells.