Kageyama Kazunori, Iwasaki Yasumasa, Watanuki Yutaka, Niioka Kanako, Daimon Makoto
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
Department of Clinical Nutrition Management Nutrition Course, Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie 510-0293, Japan.
Int J Mol Sci. 2021 May 27;22(11):5724. doi: 10.3390/ijms22115724.
The hypothalamic-pituitary-adrenal axis is stimulated in response to stress. When activated, it is suppressed by the negative feedback effect of glucocorticoids. Glucocorticoids directly inhibit () gene expression in the pituitary. Glucocorticoid signaling is mediated via glucocorticoid receptors, 11β-hydroxysteroid dehydrogenases, and the FK506-binding immunophilins, Fkbp4 and Fkbp5. Fkbp4 and Fkbp5 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor, resulting in modulation of the glucocorticoid action. Here, we explored the regulation of and genes and their proteins with dexamethasone, a major synthetic glucocorticoid drug, in murine AtT-20 corticotroph cells. To elucidate further roles of Fkbp4 and Fkbp5, we examined their effects on mRNA levels in corticotroph cells. Dexamethasone decreased mRNA levels as well as mRNA levels in mouse corticotroph cells. Dexamethasone tended to decrease Fkbp4 protein levels, while it increased mRNA and its protein levels. The dexamethasone-induced decreases in mRNA levels were partially canceled by knockdown. Alternatively, mRNA levels were further decreased by knockdown. Thus, Fkbp4 contributes to the negative feedback of glucocorticoids, and Fkbp5 reduces the efficiency of the glucocorticoid effect on gene expression in pituitary corticotroph cells.
下丘脑 - 垂体 - 肾上腺轴在应激反应中被激活。激活后，它会受到糖皮质激素负反馈作用的抑制。糖皮质激素直接抑制垂体中的（）基因表达。糖皮质激素信号通过糖皮质激素受体、11β - 羟基类固醇脱氢酶以及FK506结合亲免素Fkbp4和Fkbp5介导。Fkbp4和Fkbp5对动力蛋白与糖皮质激素受体的相互作用及核转位有不同的调节作用，从而导致糖皮质激素作用的调节。在此，我们在小鼠AtT - 20促肾上腺皮质激素细胞中，研究了主要合成糖皮质激素药物地塞米松对（）基因及其蛋白的调节作用。为了进一步阐明Fkbp4和Fkbp5的作用，我们检测了它们对促肾上腺皮质激素细胞中（）mRNA水平的影响。地塞米松降低了小鼠促肾上腺皮质激素细胞中的（）mRNA水平以及（）mRNA水平。地塞米松倾向于降低Fkbp4蛋白水平，而它增加了（）mRNA及其蛋白水平。地塞米松诱导的（）mRNA水平降低被（）敲低部分抵消。或者，（）敲低进一步降低了（）mRNA水平。因此，Fkbp4有助于糖皮质激素的负反馈，而Fkbp5降低了糖皮质激素对垂体促肾上腺皮质激素细胞中（）基因表达的作用效率。
