Ray D W, Ren S G, Melmed S
Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine 90048, USA.
Ann N Y Acad Sci. 1998 May 1;840:162-73. doi: 10.1111/j.1749-6632.1998.tb09560.x.
Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in both fetal and adult pituitary tissue, and LIF immunoreactivity is found in functional human pituitary tumors. LIF induces basal, and augments CRH-induced, POMC mRNA and ACTH secretion from AtT20 cells. Therefore, we examined LIF signaling and LIF regulation of POMC expression in AtT20 cells. Immunoneutralization studies demonstrated the dependence of LIF action on both the specific LIF receptor (35% inhibition; p < 0.05) and also the gpl30 affinity converter (41% inhibition; p < 0.05). These antisera also attenuate basal ACTH secretion without added LIF. LIF rapidly induced tyrosyl phosphorylation of both STAT 1 alpha, and STAT beta and also induced phosphorylation of a novel STAT 1 alpha related protein p115. LIF induced POMC transcription (-706/+64) and strikingly potentiated CRH action (up to 18-fold induction). This synergy involved cAMP-dependent pathways, as forskolin action was also potentiated by LIF. Deletion of the major CRH-responsive region in POMC (-323/-166) abolished both CRH and LIF action on POMC transcription. Thus LIF action in pituitary corticotrophs is dependent on LIF receptor heterodimerisation with gpl30 and involves STAT protein tyrosyl phosphorylation. LIF enhances POMC transcription and strongly potentiates the well-documented action of CRH on the POMC gene. These results define a subcellular mechanism for an immuno-neuroendocrine interface between peripheral afferent signals and the HPA axis.
白血病抑制因子（LIF）是一种多效性细胞因子，在胎儿和成人垂体组织中均有表达，并且在功能性人垂体肿瘤中可发现LIF免疫反应性。LIF诱导AtT20细胞中阿黑皮素原（POMC）mRNA的基础表达，并增强促肾上腺皮质激素释放激素（CRH）诱导的POMC mRNA表达及促肾上腺皮质激素（ACTH）分泌。因此，我们研究了AtT20细胞中LIF信号传导及LIF对POMC表达的调控。免疫中和研究表明，LIF的作用依赖于特异性LIF受体（抑制率35%；p<0.05）以及糖蛋白130（gp130）亲和力转换器（抑制率41%；p<0.05）。这些抗血清在未添加LIF的情况下也会减弱基础ACTH分泌。LIF迅速诱导信号转导和转录激活因子1α（STAT 1α）及信号转导和转录激活因子1β（STATβ）的酪氨酸磷酸化，还诱导一种新型的与STAT 1α相关的蛋白p115的磷酸化。LIF诱导POMC转录（-706/+64），并显著增强CRH的作用（诱导倍数高达18倍）。这种协同作用涉及环磷酸腺苷（cAMP）依赖性途径，因为LIF也增强了福斯可林的作用。POMC中主要的CRH反应区域（-323/-166）缺失消除了CRH和LIF对POMC转录的作用。因此，垂体促肾上腺皮质细胞中LIF的作用依赖于LIF受体与gp130的异二聚化，并涉及STAT蛋白的酪氨酸磷酸化。LIF增强POMC转录，并强烈增强CRH对POMC基因的作用。这些结果确定了外周传入信号与下丘脑-垂体-肾上腺（HPA）轴之间免疫-神经内分泌界面的亚细胞机制。
