The crosstalk between the nervous, immune and endocrine systems and its role for immune diseases

我们研究了神经系统、免疫系统和内分泌系统之间的串扰。神经营养因子包括神经生长因子（NGF）、脑源性神经营养因子（BDNF）和神经营养因子-3 (NT-3)，是神经系统发育的重要因子。然而，在这里，我们证明了神经肽、神经营养因子及其受体在由ova特异性D011.10 TCR转基因小鼠的CD4^+CD45RB^+ T细胞诱导的Th1和Th2细胞中的基因表达。有趣的是，pre - proenkephalin （PPE）基因在Th2细胞中被特异性诱导，而在Th1细胞中不被特异性诱导。此外，研究表明，编码NT-3高亲和力受体的TrkC基因在Th2细胞中选择性表达，而在Th1和初始CD4^+ T细胞中不表达。在培养物中加入抗ifn -g单抗可显著增强TrkC基因的表达，而抗il -4单抗可阻断TrkC基因的表达。此外，NT-3协同增强抗cd3单抗诱导的Th2细胞产生IL-4，但不影响Th1细胞产生IFN-g。这些数据表明NT-3通过其受体TrkC在调节Th1/Th2平衡中起关键作用。我们还发现Th2细胞而不是Th1细胞表达功能P450ssc和20a-HSD基因，这是甾体生成和代谢物的关键酶。将胆固醇添加到Th2细胞培养中导致类固醇前体progenolone的产生。Th2细胞不能自行代谢孕酮生成孕酮。然而，如果它们与表达功能性3b-HSD基因的基质细胞共存，则产生显著水平的黄体酮。此外，黄体酮被证明可以刺激幼稚Th细胞向Th2细胞的极化。由此可见，Th2细胞产生的免疫类固醇参与了免疫平衡的调节。

We investigated the crosstalk between nervous, immune and endocrine systems. Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are essential factors for the development of the nervous system. However, here, we demonstrate gene expression of neuropeptide, neurotrophins and their receptors in Th1 and Th2 cells induced from naive CD4^+CD45RB^+ T cells from OVA-specific D011.10 TCR transgenic mice. Interestingly, preproenkephalin (PPE) gene is specifically induced in Th2 cells but not in Th1 cells. Moreover, it is demonstrated that TrkC gene, which encodes a high affinity receptor for NT-3, was selectively expressed in Th2 cells, but not in Th1 and naive CD4^+ T cells. Expression of the TrkC gene was markedly augmented by addition of anti-IFN-g mAb into the culture, whereas it was blocked by anti-IL-4 mAb. Moreover, NT-3 synergistically enhanced anti-CD3 mAb-induced IL-4 production by Th2 cells, but did not affect IFN-g production by Th1 cells. These data suggest that NT-3, through its receptor TrkC, plays a critical role in regulating the Th1/Th2 balance.We also found that Th2 cells but not Th1 cells expressed functional P450ssc and 20a-HSD genes, which are critical enzymes for steroidgenesis and metabolite. Addition of cholesterol into Th2 cell-culture resulted in generation of steroid precursor, prognenolone. Th2 cells did not metabolite prognenolone to generate progesterone by themselves. However, if they were co-existed with stroma cells which express functional 3b-HSD gene, significant levels of progesterone were produced. Moreover, progesterone is shown to stimulate the polarization of naive Th cells into Th2 cells. Thus, it was demonstrated that immune steroid produced by Th2 cells is involved in the regulation of immune balance.