PhosphoCREB and CREM/ICER - Positive and negative regulation of proenkephalin gene expression in the paraventricular nucleus of the hypothalamus

In the hypothalamic paraventricular nucleus (PVN), the proenkephalin gene m ay be upregulared by lipopolysaccharide (LPS) and downregulated by the GABA -A agonist muscimol. Candidate transcription factors regulating the proenke phalin gene in opposite directions are cAMP-response-element-binding protei n (CREB) (when phosphorylated, a positive regulator) and cAMP-responsive mo dulatory inducible cAMP early repressor (CREM/ICER) (a negative regulator). Our results demonstrate that CREM alpha,beta,gamma transcripts and ICER ar e induced in the PVN by LPS and remain elevated for periods of up to 12 h. PhosphoCREB is elevated after LPS administration, peaking at 8 h, but remai ning elevated over control levels at 12 h. PhosphoCREB induction by LPS is also seen in primary hypothalamic cultures. Cotransfection of ICER with ENK -CAT12 into primary hypothalamic cultures produced a decrease in chloramphe nicol acetyl transferase (CAT) levels following cAMP or LPS stimulation. Ph osphoCREB is downregulated and CREM/ICER is upregulated in the PVN by musci mol suggesting that the regulation of these transcription factors may under lie the inhibitory effect of muscimol on target genes in the PVN.