PMID- 31666193 OWN - NLM STAT- MEDLINE DCOM- 20200219 LR - 20200219 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 101 DP - 2019 Dec TI - Interleukin-1alpha leads to growth hormone deficiency in adamantinomatous craniopharyngioma by targeting pericytes: implication in pituitary fibrosis. PG - 153998 LID - S0026-0495(19)30213-6 [pii] LID - 10.1016/j.metabol.2019.153998 [doi] AB - 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-1alpha (IL-1alpha) 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-1alpha 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-1alpha acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1alpha (rrIL-1alpha) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 mul/h over 28 days, and then the effects of IL-1alpha treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1alpha 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-1alpha, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1alpha 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-1alpha significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1alpha was mediated by the IL-1R1 signaling pathway. In vivo, IL-1alpha 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-1alpha signaling might be a potential therapy for GHD in aCP. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Mao, Jian AU - Mao J AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Qiu, Binghui AU - Qiu B AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Mei, Fen AU - Mei F AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Liu, Fan AU - Liu F AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Feng, Zhanpeng AU - Feng Z AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Fan, Jun AU - Fan J AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Nie, Jing AU - Nie J AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Huang, Lijun AU - Huang L AD - The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Liao, Xixian AU - Liao X AD - The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Wang, Zhenhao AU - Wang Z AD - The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Zeng, Jiahui AU - Zeng J AD - The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Weng, Zelin AU - Weng Z AD - The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Zang, Nailiang AU - Zang N AD - The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Qi, Songtao AU - Qi S AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: qisongtaonfyy@126.com. FAU - Bao, Yun AU - Bao Y AD - Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: baoyun519@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191027 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Cytokines) RN - 0 (IL1A protein, human) RN - 0 (Interleukin-1alpha) RN - 12629-01-5 (Human Growth Hormone) SB - IM MH - Adult MH - Animals MH - *Cell Communication MH - Craniopharyngioma/etiology/*pathology MH - Cytokines/metabolism MH - Female MH - Fibrosis MH - Human Growth Hormone/*deficiency/drug effects/metabolism MH - Humans MH - Inflammation MH - Interleukin-1alpha/*pharmacology MH - Male MH - Pericytes/cytology/*drug effects MH - Pituitary Gland/metabolism/pathology MH - Rats OTO - NOTNLM OT - Adamantinomatous craniopharyngioma OT - Growth hormone deficiency OT - Interleukin-1alpha OT - Pericytes OT - Pituitary fibrosis EDAT- 2019/11/02 06:00 MHDA- 2020/02/20 06:00 CRDT- 2019/11/01 06:00 PHST- 2019/07/09 00:00 [received] PHST- 2019/09/18 00:00 [revised] PHST- 2019/09/20 00:00 [accepted] PHST- 2019/11/02 06:00 [pubmed] PHST- 2020/02/20 06:00 [medline] PHST- 2019/11/01 06:00 [entrez] AID - S0026-0495(19)30213-6 [pii] AID - 10.1016/j.metabol.2019.153998 [doi] PST - ppublish SO - Metabolism. 2019 Dec;101:153998. doi: 10.1016/j.metabol.2019.153998. Epub 2019 Oct 27.