Borsook D, Smirnova O, Behar O, Lewis S, Kobierski L A
Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
J Mol Neurosci. 1999 Feb;12(1):35-51. doi: 10.1385/JMN:12:1:35.
In the hypothalamic paraventricular nucleus (PVN), the proenkephalin gene may be upregulated by lipopolysaccharide (LPS) and downregulated by the GABA-A agonist muscimol. Candidate transcription factors regulating the proenkephalin gene in opposite directions are cAMP-response-element-binding protein (CREB) (when phosphorylated, a positive regulator) and cAMP-responsive modulatory inducible cAMP early repressor (CREM/ICER) (a negative regulator). Our results demonstrate that CREM alpha,beta,gamma transcripts and ICER are 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 remaining elevated over control levels at 12 h. Phospho-CREB induction by LPS is also seen in primary hypothalamic cultures. Cotransfection of ICER with ENK-CAT12 into primary hypothalamic cultures produced a decrease in chloramphenicol acetyl transferase (CAT) levels following cAMP or LPS stimulation. PhosphoCREB is downregulated and CREM/ICER is upregulated in the PVN by muscimol, suggesting that the regulation of these transcription factors may underlie the inhibitory effect of muscimol on target genes in the PVN.
在下丘脑室旁核（PVN）中，前脑啡肽原基因可能被脂多糖（LPS）上调，并被GABA-A激动剂蝇蕈醇下调。以相反方向调节前脑啡肽原基因的候选转录因子是环磷酸腺苷反应元件结合蛋白（CREB）（磷酸化时为正调节因子）和环磷酸腺苷反应调节诱导性环磷酸腺苷早期阻遏物（CREM/ICER）（负调节因子）。我们的结果表明，LPS可诱导PVN中CREMα、β、γ转录本和ICER的表达，并在长达12小时的时间内保持升高。LPS给药后磷酸化CREB升高，在8小时达到峰值，但在12小时时仍高于对照水平。在原代下丘脑培养物中也可见LPS诱导的磷酸化CREB。将ICER与ENK-CAT12共转染到原代下丘脑培养物中，在环磷酸腺苷或LPS刺激后，氯霉素乙酰转移酶（CAT）水平降低。蝇蕈醇可使PVN中的磷酸化CREB下调，CREM/ICER上调，这表明这些转录因子的调节可能是蝇蕈醇对PVN中靶基因抑制作用的基础。
