Ait-Ali Djida, Turquier Valerie, Grumolato Luca, Yon Laurent, Jourdain Matthieu, Alexandre David, Eiden Lee E, Vaudry Hubert, Anouar Youssef
European Institute for Peptide Research (IFRMP 23), Institut National de la Santé et de la Recherche Médicale Unité 413, Unité Associée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France.
Mol Endocrinol. 2004 Jul;18(7):1721-39. doi: 10.1210/me.2003-0129. Epub 2004 Apr 15.
Immune-autonomic interactions are known to occur at the level of the adrenal medulla, and to be important in immune and stress responses, but the molecular signaling pathways through which cytokines actually affect adrenal chromaffin cell function are unknown. Here, we studied the effects of the proinflammatory cytokines, TNF-alpha and IL-1, on gene transcription and secretion of bioactive neuropeptides, in primary bovine adrenochromaffin cells. TNF-alpha and IL-1 induced a time- and dose-dependent increase in galanin, vasoactive intestinal polypeptide, and secretogranin II mRNA levels. The two cytokines also stimulated the basal as well as depolarization-provoked release of enkephalin and secretoneurin from chromaffin cells. Stimulatory effects of TNF-alpha on neuropeptide gene expression and release appeared to be mediated through the type 2 TNF-alpha receptor, and required activation of ERK 1/2 and p38, but not Janus kinase, MAPKs. In addition, TNF-alpha increased the binding activity of activator protein-1 (AP-1) and stimulated transcription of a reporter gene containing AP-1-responsive elements in chromaffin cells. The AP-1-responsive reporter gene could also be activated through the ERK pathway. These results suggest that neuropeptide biosynthesis in chromaffin cells is regulated by TNF-alpha via an ERK-dependent activation of AP-1-responsive gene elements. Either locally produced or systemic cytokines might regulate biosynthesis and release of neuropeptides in chromaffin cells, integrating the adrenal medulla in the physiological response to inflammation. This study describes, for the first time, a signal transduction pathway activated by TNF-alpha in a major class of neuroendocrine cells that, unlike TNF-alpha signaling in lymphoid cells, employs ERK and p38 rather than Janus kinase and p38 to transmit gene-regulatory signals to the cell nucleus.
免疫与自主神经系统的相互作用已知发生在肾上腺髓质水平，且在免疫和应激反应中起重要作用，但细胞因子实际影响肾上腺嗜铬细胞功能的分子信号通路尚不清楚。在此，我们研究了促炎细胞因子TNF-α和IL-1对原代牛肾上腺嗜铬细胞中生物活性神经肽基因转录和分泌的影响。TNF-α和IL-1诱导甘丙肽、血管活性肠肽和分泌粒蛋白II mRNA水平呈时间和剂量依赖性增加。这两种细胞因子还刺激了嗜铬细胞中脑啡肽和分泌素原的基础释放以及去极化引发的释放。TNF-α对神经肽基因表达和释放的刺激作用似乎是通过2型TNF-α受体介导的，并且需要ERK 1/2和p38的激活，但不需要Janus激酶、丝裂原活化蛋白激酶（MAPK）。此外，TNF-α增加了激活蛋白-1（AP-1）的结合活性，并刺激了嗜铬细胞中含有AP-1反应元件的报告基因的转录。AP-1反应报告基因也可以通过ERK途径激活。这些结果表明，嗜铬细胞中的神经肽生物合成受TNF-α通过ERK依赖性激活AP-1反应基因元件的调控。局部产生的或全身性的细胞因子可能调节嗜铬细胞中神经肽的生物合成和释放，使肾上腺髓质参与对炎症的生理反应。本研究首次描述了TNF-α在一类主要的神经内分泌细胞中激活的信号转导途径，与淋巴细胞中的TNF-α信号传导不同，该途径采用ERK和p38而不是Janus激酶和p38将基因调控信号传递到细胞核。
