Novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) stimulates corticotroph function via a signal transducer and activator of transcription-dependent mechanism negatively regulated by suppressor of cytokine signaling-3
Novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) stimulates corticotroph function via a signal transducer and activator of transcription-dependent mechanism negatively regulated by suppressor of cytokine signaling-3
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DOI：
10.1210/en.2002-220933
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发表时间：
2003-04-01
期刊：
影响因子：
4.8
通讯作者：
Engelhardt, D
中科院分区：
文献类型：
--
作者：
Auernhammer, CJ;Isele, NB;Engelhardt, D
新型神经营养因子-1/B细胞刺激因子-3(NNT-1/BSF-3)是新近克隆的一种gp130细胞因子，通过睫状神经营养因子受体(CNTFR)α/白血病抑制因子受体(LIFR)/gp130受体复合体发挥作用。本研究的目的是探讨NNT-1/BSF-3在促肾上腺皮质激素细胞功能中的作用，并进一步研究NNT-1/BSF-3信号转导途径。RT-PCR检测到小鼠促肾上腺皮质激素ATT-20细胞和小鼠脑垂体组织表达睫状神经营养因子受体α、白血病抑制因子受体和gp130。ATT-20细胞与10 ng/ml重组人NNT-1/BSF-3孵育5分钟和10分钟后，迅速诱导信号转导和转录激活因子(STAT)3和STAT1的酪氨酸磷酸化。NNT-1/BSF-3 4.0+/-0.3倍和5.9+/-0.2倍显著刺激原阿片黑素皮质素启动子活性和细胞因子信号转导抑制因子-3启动子活性。与未经处理的对照组相比，NNT-1/BSF-3在24和48h显著刺激ACTH的分泌，分别是基线的1.7+/-0.2倍和1.5+/-0.1倍。与模型细胞相比，稳定过表达SOCS-3可阻断NNT-1/BSF-3诱导的STAT1和STAT3磷酸化，并几乎完全抑制STAT依赖的前阿片黑素皮质素启动子和SOCS-3启动子活性。此外，SOCS-3过表达可显著抑制NNT-1/BSF-3诱导的48h ACTH分泌。综上所述，我们已经证明NNT-1/BSF-3是促肾上腺皮质细胞功能的调节器，其功能受SOCS-3的负性调节。我们的数据表明，Jak-STAT级联的激活对于促肾上腺皮质激素NNT-1/BSF-3信号是必不可少的。进一步的研究将不得不探讨NNT-1/BSF-3作为下丘脑-垂体-肾上腺轴应激反应的神经免疫内分泌调节剂在体内的可能作用。
Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3) is a recently cloned gp130 cytokine, acting through the tripartite ciliary neurotrophic factor receptor (CNTFR) alpha/leukemia inhibitory factor receptor (LIFR)/gp130 receptor complex. The aim of the current study was to investigate the role of NNT-1/BSF-3 in corticotroph cell function and further characterize NNT-1/BSF-3 signaling pathways. Using RTPCR, expression of ciliary neurotrophic factor receptor alpha, leukemia inhibitory factor receptor, and gp130 could be demonstrated in mRNA derived from murine corticotroph AtT-20 cells and murine pituitary tissue. Incubation of AtT-20 cells with 10 ng/ml recombinant human NNT-1/BSF-3 rapidly induced tyrosine-phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT1 at 5 and 10 min. Proopiomelanocortin promoter activity and suppressor of cytokine signaling (SOCS)-3 promoter activity were significantly stimulated by NNT-1/BSF-3 4.0 +/- 0.3- and 5.9 +/- 0.2-fold, respectively. In comparison with untreated control, NNT-1/BSF-3 significantly stimulated ACTH secretion at 24 and 48 h 1.7 +/- 0.2-fold and 1.5 +/- 0.1-fold above baseline. In comparison with mock-transfected cells, stable overexpression of SOCS-3 in AtT-20 cells abolished NNT-1/BSF-3-induced STAT1 and STAT3 phosphorylation and almost completely inhibited STAT-dependent proopiomelanocortin promoter and SOCS-3 promoter activities. In addition, NNT-1/BSF-3-induced ACTH secretion at 48 h was significantly attenuated by SOCS-3 overexpression. In summary, we have shown that NNT-1/BSF-3 is a modulator of corticotroph cell function, which is negatively regulated by SOCS-3. Our data indicate that the activation of the Jak-STAT cascade is essential for corticotroph NNT-1/BSF-3 signaling. Further studies will have to investigate the possible in vivo role of NNT-1/BSF-3 as a neuroimmunoendocrine modulator of hypothalamus-pituitary-adrenal axis stress response.