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Interleukin-1α leads to growth hormone deficiency in adamantinomatous craniopharyngioma by targeting pericytes: implication in pituitary fibrosis.
Metabolism ( IF 9.8 ) Pub Date : 2019-10-27 , DOI: 10.1016/j.metabol.2019.153998
Jian Mao 1 , Binghui Qiu 1 , Fen Mei 1 , Fan Liu 1 , Zhanpeng Feng 1 , Jun Fan 1 , Jing Nie 1 , Lijun Huang 2 , Xixian Liao 2 , Zhenhao Wang 2 , Jiahui Zeng 2 , Zelin Weng 2 , Nailiang Zang 2 , Songtao Qi 1 , Yun Bao 1
Affiliation  

BACKGROUND The incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. MATERIALS AND METHODS To diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 μl/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. RESULTS There was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = 0.001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P < 0.001, F = 6.251 in tumor tissue; P = 0.003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. CONCLUSION This study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.

中文翻译:

白细胞介素-1α通过靶向周细胞而导致金刚烷性颅咽管瘤的生长激素缺乏:提示垂体纤维化。

背景技术在金刚痣性颅咽管瘤(aCP)中,生长激素缺乏症(GHD)的发生率显着高于其他鞍区肿瘤,但可能的机制仍难以捉摸。高水平的炎症反应是aCP的另一个特征。我们研究了白介素-1α(IL-1α)与GHD之间的内部联系,同时重点研究了其在垂体纤维化中的生物学活性。材料和方法为诊断GHD,在15名aCP患者进行胰岛素刺激试验后,记录其体重指数(BMI),胰岛素样生长因子-1(IGF-1)和峰值生长激素(GH)值。对aCP样品进行组织学染色。使用Millipore磁珠阵列检测肿瘤组织和细胞上清液中9种促炎细胞因子的水平。在体内和体外评估IL-1α对GH分泌的影响。使用蛋白质印迹,qRT-PCR和细胞功能分析来探讨IL-1α通过其作用于GH分泌的潜在机制。立体定向ALZET渗透泵技术用于模拟大鼠促炎细胞因子的aCP分泌。从aCP细胞上清液中制备的重组IL-1α(rrIL-1α)和条件培养基(CM)在28天之内以1μl/ h的速率直接输注至浆膜内,然后产生IL-1α的作用测定垂体的病理变化和GH的分泌。为了进一步确认IL-1α是否会通过IL-1R1影响GH分泌,从第一天起至第28天,皮下注射IL-1R1阻滞剂(IL-1R1a,10 mg / kg体重,每天一次)。结果垂体纤维化与GHD呈显着正相关(rS = 0.756,P = 0.001)。在肿瘤组织和细胞上清液中,许多细胞因子,特别是IL-1α,白介素8(IL-8)和单核细胞趋化蛋白1(MCP-1)升高。GIL组和No-GHD组之间只有IL-1α表现出显着差异(肿瘤组织中P <0.001,F = 6.251;细胞上清液中P = 0.003,F = 1.529)。IL-1α显着降低了GH3和周细胞共培养中的GH分泌。IL-1R信号转导通路介导了IL-1α诱导的周细胞活化。在体内,IL-1α诱导垂体纤维化,进一步导致GH水平降低。IL-1R1a拮抗这种病理变化。结论本研究发现垂体aCP细胞与基质细胞之间的串扰,
更新日期:2019-10-27
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