Pituitary corticotroph SOCS-3: Novel intracellular regulation of leukemia-inhibitory factor-mediated proopiomelanocortin gene expression and adrenocorticotropin secretion
Pituitary corticotroph SOCS-3: Novel intracellular regulation of leukemia-inhibitory factor-mediated proopiomelanocortin gene expression and adrenocorticotropin secretion
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DOI：
10.1210/me.12.7.954
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发表时间：
1998-07-01
影响因子：
--
通讯作者：
Melmed, S
中科院分区：
文献类型：
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作者：
Auernhammer, CJ;Chesnokova, V;Melmed, S
由于垂体白血病抑制因子（垂体白血病抑制因子）介导下丘脑垂体肾上腺轴的神经免疫信号，我们测试了细胞内SOCS-3在促皮质功能中的作用。SOCS-3是细胞因子信号抑制因子（SOCS）家族的细胞因子诱导蛋白，在小鼠垂体体内表达。经ip注射LIF （5.0 μ g/小鼠）或白细胞介素-1 β （0.1 μ g/小鼠）后，垂体SOCS-3 mRNA分别被刺激了9倍和6倍。此外，在促皮质细胞at -20中，LIF和白细胞介素-1 β都能刺激SOCS-3 mRNA的表达。在at -20细胞中，与模拟转染的at -20细胞相比，SOCS-3的稳定过表达抑制了基础和liff刺激的ACTH分泌（基础：4426 +/- 118比4973 +/- 138 pg/ml， P < 0.05； liff诱导：5511 +/- 172比9308 +/- 465 pg/ml， P < 0.001）。在at -20细胞中稳定过表达SOCS-3 cDNA也导致liff诱导的POMC mRNA水平和POMC启动子活性分别显著降低50% （P < 0.05）和50% （P < 0.001）。Western blot分析显示，在过表达at -20的SOCS-3细胞中，liff刺激的gp130和STAT-3磷酸化受到抑制。因此，SOCS-3抑制Janus激酶（JAK）和信号转导和转录激活因子（STAT）通路，已知其介导liff刺激的ACTH分泌和POMC基因表达。综上所述，SOCS-3是细胞内POMC基因表达和ACTH分泌的调节因子，是细胞因子介导的神经-免疫-内分泌界面的负反馈介质。
As pituitary leukemia-inhibitory factor (LIF) mediates neuroimmune signals to the hypothalamopituitary-adrenal axis, we tested the role of intracellular SOCS-3 in corticotroph function. SOCS-3, a cytokine-inducible protein of the suppressor of cytokine signaling (SOCS) family, is expressed in the murine pituitary in vivo. After ip injection of LIF (5.0 mu g/mouse) or interleukin-1 beta (0.1 mu g/mouse) pituitary SOCS-3 mRNA was stimulated 9-fold and 6-fold, respectively. Also, in corticotroph AtT-20 cells LIF and interleukin-1 beta both potently stimulated SOCS-3 mRNA expression. In AtT-20 cells, stable overexpression of SOCS-3 inhibits basal and LIF-stimulated ACTH secretion in comparison to mock-transfected AtT-20 cells (basal: 4426 +/- 118 vs. 4973 +/- 138 pg/ml, P < 0.05; LIF-induced: 5511 +/- 172 vs. 9308 +/- 465 pg/ml, P < 0.001). Stable overexpression of SOCS-3 cDNA in AtT-20 cells also resulted in a significant 50% decrease of LIF-induced POMC mRNA levels (P < 0.05) and POMC promoter activity (P < 0.001), respectively. Western blot analysis revealed an inhibition of LIF-stimulated gp130 and STAT-3 phosphorylation in SOCS-3 overexpressing AtT-20 cells. Thus, SOCS-3 inhibits the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathway, which is known to mediate LIF-stimulated ACTH secretion and POMC gene expression. In conclusion, SOCS-3 functions as an intracellular regulator of POMC gene expression and ACTH secretion, acting as a negative feedback mediator of the cytokine-mediated neuro-immuno-endocrine interface.