Shimon I, Yan X, Ray D W, Melmed S
Department of Medicine, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
J Clin Invest. 1997 Jul 15;100(2):357-63. doi: 10.1172/JCI119541.
We have shown recently that leukemia inhibitory factor (LIF) and oncostatin M (OSM), two members of the gp130-dependent cytokine family, stimulate murine proopiomelanocortin (POMC) transcription and adrenocorticotropin hormone (ACTH) secretion. LIF and corticotropin-releasing hormone (CRH) also synergistically induced in vivo ACTH secretion in fetal nonhuman primates. To elucidate the role of the gp130-related cytokines in human pituitary hormone regulation, we tested expression of gp130-related cytokine receptors in human fetal pituitaries. Using RT-PCR, mRNA expression of receptors for LIF, IL-6, and CRH, and the gp130 subunit, were all detected in fetal pituitaries of 18- and 31-wk gestation. Recombinant human IL-6, LIF, and OSM treatments of primary human fetal pituitary cultures (16-31 wk) increased ACTH secretion by up to 48% (P < 0.05) using doses of 1 nM, and when fetal cultures were cotreated with CRH, ACTH was induced five- to sixfold as compared to CRH alone (three- to fourfold; P = 0.01). Incubation with gp130-specific antibody suppressed basal and cytokine-stimulated ACTH secretion (alone or with CRH) from human fetal cells. Human POMC promoter -879/+6 fused to the luciferase reporter gene and transfected into AtT-20 cells, was stimulated by LIF (7-fold), which also exerted strong (22-fold) synergy with CRH on POMC transcription. Growth hormone (GH) release from fetal cultures was modestly stimulated (15-31%, P < 0.05), while other anterior pituitary hormones were not altered by these cytokines. Thus, physiologic concentrations of the gp130-related cytokines have direct effects on ACTH and GH regulation in the human pituitary, indicating that gp130-dependent signals serve as a paracrine system controlling early human pituitary function.
我们最近发现，白血病抑制因子（LIF）和抑瘤素M（OSM）这两种gp130依赖性细胞因子家族成员，可刺激小鼠阿黑皮素原（POMC）转录及促肾上腺皮质激素（ACTH）分泌。LIF和促肾上腺皮质激素释放激素（CRH）在胎儿非人灵长类动物体内也能协同诱导ACTH分泌。为阐明gp130相关细胞因子在人类垂体激素调节中的作用，我们检测了人类胎儿垂体中gp130相关细胞因子受体的表达。采用逆转录聚合酶链反应（RT-PCR），在妊娠18周和31周的胎儿垂体中均检测到LIF、白细胞介素-6（IL-6）、CRH受体及gp130亚基的mRNA表达。用重组人IL-6、LIF和OSM处理原代人类胎儿垂体培养物（16 - 31周），使用1 nM剂量时可使ACTH分泌增加高达48%（P < 0.05），当胎儿培养物与CRH共同处理时，与单独使用CRH相比，ACTH诱导增加了五至六倍（单独使用CRH时为三至四倍；P = 0.01）。用gp130特异性抗体孵育可抑制人类胎儿细胞基础及细胞因子刺激的ACTH分泌（单独或与CRH共同刺激）。与荧光素酶报告基因融合并转染至AtT-20细胞的人类POMC启动子-879 / +6，受到LIF刺激（7倍），LIF在POMC转录方面也与CRH产生强烈协同作用（22倍）。胎儿培养物中生长激素（GH）释放受到适度刺激（15 - 31%，P < 0.05），而其他垂体前叶激素未受这些细胞因子影响。因此，gp130相关细胞因子的生理浓度对人类垂体中ACTH和GH调节有直接作用，表明gp130依赖性信号作为旁分泌系统控制人类早期垂体功能。
