The study on the regulation of CRF and ACTH related peptides

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To study the regulatiory mechanism of the hypothalamic (CRF) -anterior pituitary (ACTH) -adrenal (cortisol) axis, we examined a short feedback effect of ACTH-related peptide on it, the role of immediately early gene products (FOS,JUN) and a cAMP response element-binding protein (CREB) in stress-indued CRF and POMC (a precursor for ACTH) gene expression, and regulatory mechanism of human plasma CRF-binding protein. Results are as follows ;1. The elevation of mRNA levels of c-fos and c-jun in the hypothalamus and the anterior pituitary was found prior to the elevation of stress-induced CRF and POMC mRNA levels. However, the treatment with antisense oligonucleotides to c-jun or c-fos failed to affect stress-induced CRF mRNA levels, but inhibited CRF-induced POMC gene expression.2. Treatment with antisense oligo to CREB inhibited stress-induced CRF gene expression in the hypothalamus.3. Neuropeptide Y,angiotensin II and noradrenaline stimulated CRF gene expression in the hypothalamus, while beta-endorphin and alphaMSH inhibited it.4. There was a negative correlatoion between levels of CRF-binding protein and those of cortisol in the human plasma. In addition, iv bolus injection of hCRF stimulated dimerization of CRF-binding protein.These results suggested as follows ;1. The A-kinase-CREB system seems to have an important role in the CRF and POMC gene expression.2. AP-1 has a little effect on CRF gene expression in the hypothalamus.3. CRF-binding protein is down-regulated by chronic hypercortisolemia and makes an own homodimer after hCRF administration. Such similarity to some kinds of receptor should be clarified in the future.