The study on the regulation of CRF and ACTH related peptides

为了研究下丘脑(CRF)-垂体前叶(ACTH)-肾上腺(皮质醇)轴的调节机制，我们研究了ACTH相关肽对其的短反馈效应、即刻早期基因产物(FOS、JUN)和cAMP反应元件结合蛋白(CREB)在应激诱导的CRF和POMC(ACTH前体)基因表达中的作用，以及人血浆CRF结合蛋白的调节机制。结果如下：1.应激诱导的CRF和POMC中c-fos和c-jun的表达先于应激诱导的CRF和POMC的表达。但c-jun或c-fos反义寡核苷酸对应激诱导的CRF基因表达无明显影响，但可抑制CRF诱导的POMC基因表达。CREB反义寡核苷酸治疗可抑制应激诱导的下丘脑CRF基因表达。神经肽Y、血管紧张素II和去甲肾上腺素促进下丘脑CRF基因的表达，而β-内啡肽和α-MSH则抑制其表达。血浆CRF结合蛋白水平与皮质醇水平呈负相关。此外，静脉注射hCRF可刺激CRF结合蛋白的二聚化。这些结果表明：1.A-激酶-CREB系统似乎在CRF和POMC基因的表达中起重要作用。AP-1对下丘脑CRF基因表达影响不大。CRF结合蛋白在慢性高皮质醇血症中表达下调，并在hCRF治疗后形成自身同源二聚体。这种与某些受体的相似性应在未来澄清。

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.