Eskay R L, Eiden L E
Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, Bethesda, Maryland 20892.
Endocrinology. 1992 Apr;130(4):2252-8. doi: 10.1210/endo.130.4.1372239.
The pattern of expression of at least four neuropeptides contained in adrenomedullary chromaffin cells is altered by exposure to the cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF alpha), alone or in combination with stimulation of other second messenger pathways. Vasoactive intestinal polypeptide (VIP) was elevated 2- to 3-fold by 1 nM IL-1 alpha within 48 h of exposure, while neurotensin and substance P synthesis were unaffected, and met-enkephalin levels were decreased 25-35%. Stimulation of VIP and substance P biosynthesis by forskolin was markedly enhanced by IL-1 alpha, while forskolin stimulation of enkephalin and neurotensin biosynthesis was unaffected. IL-1 alpha amplified the effect of phorbol myristate acetate to increase the VIP content of chromaffin cells, but antagonized phorbol ester-induced elevation of neurotensin levels. TNF alpha also demonstrated a neuropeptide-specific pattern of modulation of second-messenger effects on chromaffin cell neuropeptide levels similar to those seen with IL-1 alpha. The neuroendocrine actions of IL-1 alpha described above, unlike IL-1 action in the immune system, do not appear to be mediated through IL-2 as this cytokine did not affect VIP or enkephalin expression in the presence or absence of protein kinase stimulation. Neither IL-1 alpha nor TNF alpha affected the calcium-coupled stimulation of neuropeptide secretion and biosynthesis that occurs in response to cell depolarization in these and other neuroendocrine cells in vitro and in vivo. These data provide a functional demonstration of IL-1 and TNF receptors in chromaffin cell cultures and suggest a physiological role for cytokine production in the adrenal medulla. Since both the magnitude and direction of neuropeptide synthesis modulation by IL-1 alpha and TNF alpha are highly peptide-specific, it appears that these cytokines do not merely augment second messenger pathways that affect neuropeptide synthesis, but potentially regulate the activity of factors controlling the pattern of neuropeptide gene expression in chromaffin cells.
肾上腺髓质嗜铬细胞中至少四种神经肽的表达模式，会因单独暴露于细胞因子白细胞介素-1α（IL-1α）和肿瘤坏死因子-α（TNFα），或与其他第二信使途径的刺激联合作用而发生改变。在暴露于1 nM IL-1α的48小时内，血管活性肠肽（VIP）升高了2至3倍，而神经降压素和P物质的合成未受影响，甲硫氨酸脑啡肽水平降低了25%至35%。IL-1α显著增强了福斯高林对VIP和P物质生物合成的刺激作用，而福斯高林对脑啡肽和神经降压素生物合成的刺激作用未受影响。IL-1α放大了佛波醇肉豆蔻酸酯增加嗜铬细胞VIP含量的作用，但拮抗了佛波酯诱导的神经降压素水平升高。TNFα也表现出对嗜铬细胞神经肽水平的第二信使效应进行神经肽特异性调节的模式，类似于IL-1α所观察到的情况。上述IL-1α的神经内分泌作用，与IL-1在免疫系统中的作用不同，似乎不是通过IL-2介导的，因为在存在或不存在蛋白激酶刺激的情况下，这种细胞因子都不影响VIP或脑啡肽的表达。在体外和体内，IL-1α和TNFα均未影响这些及其他神经内分泌细胞中因细胞去极化而发生的神经肽分泌和生物合成的钙偶联刺激。这些数据在嗜铬细胞培养物中提供了IL-1和TNF受体的功能证明，并提示细胞因子产生在肾上腺髓质中的生理作用。由于IL-1α和TNFα对神经肽合成的调节幅度和方向都具有高度的肽特异性，似乎这些细胞因子不仅仅增强影响神经肽合成的第二信使途径，还可能调节控制嗜铬细胞中神经肽基因表达模式的因子的活性。
