TRANSCRIPTION FACTOR REGULATION OF PRODYNORPHIN GENE-EXPRESSION FOLLOWING RAT HINDPAW INFLAMMATION

Both c-Fos and prodynorphin mRNA and peptide increase unilaterally in nociceptive-specific neurons in the lumbar rat spinal cord during chro nic hindpaw inflammation. To study the mechanisms underlying prodynorp hin gene expression, we examined transcription factors and their inter actions at the CRE/AP-1-like site, DYNCRE3, found in the prodynorphin gene promoter. CREB repressed while c-Fos and c-Jun activated transcri ption through the DYNCRE3 site in transient co-transfections in PC12 c ells. Following inflammation of the rat hindpaw, immunostaining demons trated a bilateral increase in phosphorylated CREB (P-CREB)-positive n eurons in the spinal cord. Gel supershift studies showed that spinal c ord extracts contained CREB, P-CREB, and phosphorylated c-Jun (P-c-Jun ) proteins that bound to the DYNCRE3 site. We propose a model in which inflammation-induced phosphorylation of CREB relieves CREB repression at the DYNCRE3 site, P-CREB binds to the c-Fos promoter, and Fos/Fra, P-CREB, and P-c-Jun interact at the DYNCRE3 site to activate prodynor phin gene transcription. (C) 1998 Elsevier Science B.V.