Kageyama Kazunori, Hanada Komaki, Iwasaki Yasumasa, Suda Toshihiro
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan.
J Endocrinol. 2009 Jun;201(3):369-76. doi: 10.1677/JOE-08-0506. Epub 2009 Mar 17.
Corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. In the hypothalamic paraventricular nucleus (PVN), CRF, produced in response to stress, stimulates the release of ACTH from the anterior pituitary. ACTH then stimulates the release of glucocorticoids from the adrenal glands; circulating glucocorticoids are critical for recovery from stress conditions. Cytokines are also implicated in the regulation of CRF expression. Among them, interleukin (IL)-6 plays a role in the regulation of CRF. Factors other than glucocorticoids are likely to be involved in limiting the stimulation of CRF during stress. Suppressor of cytokine signaling (SOCS)-3 acts as a potent negative regulator of cytokine signaling. Little is known about the ability of the inhibitory signaling pathways to limit activation of the CRF gene in parvocellular PVN neurons. Hypothalamic 4B cells are useful for exploring the mechanisms, because these cells show characteristics of the parvocellular neurons of the PVN. In the present study, we examined whether SOCS-3 is regulated by IL-6 and cAMP in hypothalamic 4B cells. We also explored the involvement of SOCS-3 in the regulation of CRF gene expression. SOCS-3 was found to be regulated by IL-6 and via the cAMP/protein kinase A pathway in the hypothalamic cells. SOCS-3 knockdown increased IL-6- or forskolin-induced CRF gene transcription and mRNA levels. Therefore, SOCS-3, induced by a cAMP stimulant and IL-6, would be involved in the negative regulation of CRF gene expression in hypothalamic cells.
促肾上腺皮质激素释放因子（CRF）在调节应激反应中起核心作用。在下丘脑室旁核（PVN）中，应激反应产生的CRF刺激垂体前叶释放促肾上腺皮质激素（ACTH）。ACTH随后刺激肾上腺释放糖皮质激素；循环中的糖皮质激素对于从应激状态中恢复至关重要。细胞因子也参与CRF表达的调节。其中，白细胞介素（IL）-6在CRF的调节中发挥作用。除糖皮质激素外，其他因素可能参与限制应激期间CRF的刺激。细胞因子信号转导抑制因子（SOCS）-3作为细胞因子信号转导的有效负调节因子。关于抑制性信号通路限制小细胞PVN神经元中CRF基因激活的能力知之甚少。下丘脑4B细胞有助于探索其机制，因为这些细胞表现出PVN小细胞神经元的特征。在本研究中，我们检测了下丘脑4B细胞中SOCS-3是否受IL-6和cAMP调节。我们还探讨了SOCS-3在CRF基因表达调节中的作用。发现SOCS-3在下丘脑细胞中受IL-6调节并通过cAMP/蛋白激酶A途径调节。敲低SOCS-3可增加IL-6或福斯可林诱导的CRF基因转录和mRNA水平。因此，由cAMP刺激物和IL-6诱导的SOCS-3将参与下丘脑细胞中CRF基因表达的负调节。
