Tumor Necrosis Factor-α Impairs Kisspeptin Signaling in Human Gonadotropin-Releasing Hormone Primary Neurons

被引：47

作者：

Sarchielli, Erica ^{[1
]}

Comeglio, Paolo ^{[4
]}

Squecco, Roberta ^{[2
]}

Ballerini, Lara ^{[3
]}

Mello, Tommaso ^{[5
]}

Guarnieri, Giulia ^{[1
]}

Idrizaj, Eglantina ^{[2
]}

Mazzanti, Benedetta ^{[3
]}

Vignozzi, Linda ^{[4
]}

Gallina, Pasquale ^{[6
]}

Maggi, Mario ^{[4
,7
]}

Vannelli, Gabriella B. ^{[1
]}

Morelli, Annamaria ^{[1
]}

机构：

[1] Univ Florence, Dept Expt & Clin Med, Sect Human Anat & Histol, I-50134 Florence, Italy

[2] Univ Florence, Dept Expt & Clin Med, Sect Physiol Sci, I-50134 Florence, Italy

[3] Univ Florence, Dept Expt & Clin Med, Cell Therapy & Transfus Med Unit, I-50134 Florence, Italy

[4] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, Sexual Med & Androl Unit, I-50134 Florence, Italy

[5] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, Gastroenterol Unit, I-50134 Florence, Italy

[6] Univ Florence, Neurosurg Sch Tuscany, Dept Surg & Translat Med, I-50139 Florence, Italy

[7] Ist Nazl Biostrutture & Biosistemi, I-00136 Rome, Italy

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2017年 / 102卷 / 01期

关键词：

BLOOD-BRAIN-BARRIER; NF-KAPPA-B; GNRH NEURONS; RAPID ACTION; EXPRESSION; HYPOTHALAMUS; OBESITY; ROLES; GENE; REPRODUCTION;

D O I：

10.1210/jc.2016-2115

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Context: Inflammatory pathways may impair central regulatory networks involving gonadotropinreleasing hormone (GnRH) neuron activity. Studies in humans are limited by the lack of human GnRH neuron cell lines. Objective: To establish an in vitro model of human GnRH neurons and analyze the effects of proinflammatory cytokines. Design: The primary human fetal hypothalamic cells (hfHypo) were isolated from 12-week-old fetuses. Responsiveness to kisspeptin, the main GnRH neurons' physiological regulator, was evaluated for biological characterization. Tumor necrosis factor alpha (TNF-alpha) was used as a proinflammatory stimulus. Main OutcomeMeasures: Expression of specific GnRH neuronmarkers by quantitative reverse transcription-polymerase chain reaction, flow cytometry, and immunocytochemistry analyses; and GnRH-releasing ability and electrophysiological changes in response to kisspeptin. Results: The primary hfHypo showed a high percentage of GnRH-positive cells (80%), expressing a functional kisspeptin receptor (KISS1R) and able to release GnRH in response to kisspeptin. TNF-alpha exposure determined a specific inflammatory intracellular signaling and reduced GnRH secretion, KISS1R expression, and kisspeptin-induced depolarizing effect. Moreover, hfHypo possessed a primary cilium, whose assembly was inhibited by TNF-alpha. Conclusion: The hfHypo cells represent a novel tool for investigations on human GnRH neuron biology. TNF-alpha directly affects GnRH neuron function by interfering with KISS1R expression and ciliogenesis, thereby impairing kisspeptin signaling.

引用

页码：46 / 56

页数：11