Tasso Mizuki, Kageyama Kazunori, Iwasaki Yasumasa, Watanuki Yutaka, Niioka Kanako, Takayasu Shinobu, Daimon Makoto
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
Peptides. 2023 Dec;170:171112. doi: 10.1016/j.peptides.2023.171112. Epub 2023 Oct 31.
Growth differentiation factor-15 (GDF15) is a stress-activated cytokine that regulates cell growth and inflammatory and stress responses. We previously reported the role and regulation of GDF15 in pituitary corticotrophs. Dexamethasone increases Gdf15 gene expression levels and production. GDF15 suppresses adrenocorticotropic hormone synthesis in pituitary corticotrophs and subsequently mediates the negative feedback effect of glucocorticoids. Here, we analyzed corticotropin-releasing factor (Crf) promoter activity in hypothalamic 4B cells transfected with promoter-driven luciferase reporter constructs. The effects of time and GDF15 concentration on Crf mRNA levels were analyzed using quantitative real-time polymerase chain reaction. Glial cell-derived neurotrophic factor family receptor α-like (GFRAL) protein is expressed in 4B cells. GDF15 increased Crf promoter activity and Crf mRNA levels in 4B cells. The protein kinase A and C pathways also contributed to the GDF15-induced increase in Crf gene expression. GDF15 stimulates GFRAL, subsequently increasing the phosphorylation of AKT, an extracellular signal-related kinase, and the cAMP response element-binding protein. Therefore, GDF15-dependent pathways may be involved in regulating Crf expression under stressful conditions in hypothalamic cells.
生长分化因子-15（GDF15）是一种应激激活的细胞因子，可调节细胞生长以及炎症和应激反应。我们之前报道了GDF15在垂体促肾上腺皮质激素细胞中的作用和调控。地塞米松可提高Gdf15基因表达水平和产量。GDF15抑制垂体促肾上腺皮质激素细胞中促肾上腺皮质激素的合成，随后介导糖皮质激素的负反馈作用。在此，我们分析了用启动子驱动的荧光素酶报告基因构建体转染的下丘脑4B细胞中促肾上腺皮质激素释放因子（Crf）启动子的活性。使用定量实时聚合酶链反应分析时间和GDF15浓度对Crf mRNA水平的影响。胶质细胞源性神经营养因子家族受体α样（GFRAL）蛋白在4B细胞中表达。GDF15增加了4B细胞中Crf启动子活性和Crf mRNA水平。蛋白激酶A和C途径也促成了GDF15诱导的Crf基因表达增加。GDF15刺激GFRAL，随后增加细胞外信号相关激酶AKT和环磷酸腺苷反应元件结合蛋白的磷酸化。因此，GDF15依赖性途径可能参与下丘脑细胞应激条件下Crf表达的调控。
