Transcriptional regulation of hypothalamic corticotropin-releasing factor gene.

Corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. Forskolin or pituitary adenylate cyclase-activating polypeptide stimulates adenylate cyclase and then increases intracellular cAMP levels in hypothalamic cells. Activation of the protein kinase A pathway leads to binding of cAMP response element (CRE)-binding protein (CREB) on the CRF promoter. Forskolin-stimulated CRF gene transcription is mediated by CRE on the CRF 5'-promoter region. Inducible cAMP-early repressor suppresses a stress response via inhibition of the cAMP-dependent CRF gene. Glucocorticoid-dependent repression of cAMP-stimulated CRF promoter activity is mediated by both nGRE and SRE in hypothalamic cells. Interleukin (IL)-6 produced in the hypothalamus stimulates the CRF gene. Suppressor of cytokine signaling-3, which is induced by a cAMP stimulant and IL-6, is involved in the negative regulation of CRF gene expression in hypothalamic cells. Such complex mechanisms would contribute to stress responses and homeostasis in the hypothalamus.