Cell Biological Compartmentation of Brain Histamine

大脑中存在多种组胺产生细胞，如神经元细胞、肥大细胞、血管内皮细胞和小胶质细胞，这使得组胺在中枢神经系统中可能的生理作用变得相当困难。为了研究脑组胺的病理生理学意义，分析各自细胞池中组胺的动态变化也是非常重要的。在这方面，我进行了以下实验，特别是细胞因子诱导组氨酸脱羧酶活性的细胞基础。以胎鼠下丘脑和大脑皮质为材料进行脑组织原代培养。培养数天后，进一步用脂多糖孵育数小时。下丘脑细胞培养的组氨酸脱羧酶活性呈剂量依赖性增加，而皮质细胞培养的组氨酸脱羧酶活性无明显变化。使用白介素1β(IL1)也得到了类似的结果。…这些结果还表明，细胞因子诱导的组胺形成活性发生在组胺能神经元，而不是小胶质细胞或其他细胞。因为组胺能神经仅限于下丘脑结节乳头核。为了证实这一结果，我使用微透析技术检测了将IL1微量注射到结节乳头核后，下丘脑前部的活体组胺释放。注射IL1可引起组胺释放增加，并呈剂量依赖性。在外周组织中，我们已经证明了IL1诱导巨噬细胞中的组氨酸脱羧酶的表达，这相当于脑中的小胶质细胞。然而，目前的结果表明，负责诱导组胺形成和释放活性的细胞是组胺能神经元。因此，脑组胺可以作为中枢神经系统中免疫系统和神经系统之间的串扰的传递器。同样有趣的是，组胺可能与阿尔茨海默病的病理生理学有关。较少

The existence of several kinds of histamine-producing cells in the brain, such as neuronal dells, mast cells, vascular endothelial cells and microglias, has made it rather difficult to elucidate possible physiological roles of histamine in the central nervous system. To investigate pathophysiological significance of brain histamine, it is also very important to analyze the dynamics of histamine in the respective cellular pools. In this respect, I conducted following experiments, especially focused on the cellular basis of cytokine-induced histidine decarboxylase activity.Primary culture of brain tissues was performed using fetal rat hypothalamus and cerebral cortex. After several days of culture, the cells were further incubated with lipopolysaccharide for several hours. The histidine decarboxylase activities in the hypothalamic cell culture increased dose dependently, however, those in the cortical culture did not change. Similar results were obtained by using interleukin 1beta(IL1). … More These results indicate that the induction of histamine forming activity by cytokine have occurred in the histaminergic neuros, but not in the microglia or other cells. Because histaminergic neuros are exclusively confined to the hypothalamic tuberomammillary nucleus. To confirm this result, I examined the in vivo histamine release form the anterior hypothalamic area after microinjection of IL1 into the tuberomammillary nucleus using a microdialysis technique. The injection of IL1 caused increase of histamine release in a dose-dependent manner. In the peripheral tissues, we have already demonstrated that IL1 induces histidine decarboxylase expression in macrophages, which are equivalent to microglias in the brain. However, present results suggest that cells responsible to the induction of histamine forming and releasing activities are histaminergic neurons. Thus, brain histamine may serve as a transmitter for the cross talk between the immune system and the nervous system in the central nervous system. It is also interesting that histamine may contribute to the pathophysiology of Alzheimer disease. Less