Interleukin and the Magnocellular Neuroendocrine System

描述（由申请人提供）：神经内分泌系统对感染和炎症期间外周释放的细胞因子作出反应。然而，新出现的证据表明，在中枢神经系统中存在表达白细胞介素-1 β (il -1 β)的内在神经系统。在大细胞神经内分泌系统中，il -1 β含有与催产素（OT）和加压素（VP）分离的分泌颗粒，指示其独立释放。这种细胞因子可能在饮用高渗盐水（2% NaCI）和哺乳的慢性刺激下调节神经垂体激素的分泌，因为所有三种多肽都从神经叶中耗尽。本研究的重点是了解白细胞介素-1 β在大细胞系统中的神经生物学作用及其与前列腺素和一氧化氮（NO）的相互作用，在调节OT从大细胞神经元的细胞体和树突及其神经叶轴突末端释放的过程中。采用免疫亲和毛细管电泳结合激光诱导荧光检测技术，对2% NaCI灌胃1、3、5、8 d后复水的大鼠和泌乳2、5、10、15、21 d后断奶的大鼠血浆中il -1 β、OT、VP及其视上核（SON）和神经叶中含量的定量关系进行了研究。通过免疫毛细管电泳和激光间接荧光检测对SON区相同微透析样品中的il -1 β、OT和VP进行定量，以检验a) il -1 β局部注入是否改变大细胞神经元树突释放OT；b)在饮用2% NaCI的1,3,5或8天内，内源性il -1 β释放发生在SON区域；c)饮用2% NaCI后，SON区域的OT和IL-1 β释放被IL-1受体拮抗剂、前列腺素合成抑制剂（甲氯芬酯）和一氧化氮合酶抑制剂（L-NAME）或神经元传导阻滞剂（河鲀毒素、ω - concontoxin GVIA和ω -agatoxin IVA）改变。最后，我们将绘制在饮用2% NaCI 2或8天后激活大细胞系统的前脑区域（皮质下器官SFO、血管终末膜、OVLT、正中视前核）的功能图谱（Fos表达；免疫组化），并确定脑室内给予IL-1受体拮抗剂是否会改变这种反应。拟议的研究将提供il -1 β在大细胞系统中的功能评估及其在慢性刺激下大细胞神经内分泌系统中枢（核内）和外周释放OT（和VP）的神经调节作用。

DESCRIPTION (provided by applicant): Neuroendocrine systems respond to cytokines released peripherally during infection and inflammation. Emerging evidence, however, reveals that within the central nervous system there are intrinsic neural systems expressing interleukin-1beta (IL-1beta). In the magnocellular neuroendocrine system, IL-1beta is contained in secretory granules separate from oxytocin (OT) and vasopressin (VP) indicative of independent release. This cytokine may modulate secretion of neurohypophysial hormones during chronic stimulation by drinking hypertonic salt water (2 percent NaCI) and by lactation, as all three peptides become depleted from the neural lobe. The proposed research is focused on understanding the neurobiology of IL-1beta in the magnocellular system and its interaction with prostaglandins and nitric oxide (NO) in the regulation of OT release from the cell bodies and dendrites of magnocellular neurons and from their axon terminals in the neural lobe. Using immunoaffinity capillary electrophoresis with laser-induced fluorescence detection, the quantitative relation-ships among IL-1beta, OT and VP in plasma and their content in the supraoptic nucleus (SON) and neural lobe will be characterized from animals that drink 2 percent NaCI for 1, 3, 5 and 8 days and are rehydrated, as well as from rats that are lactating for 2, 5, 10, 15 and 21 days and are weaned. IL-1beta, OT and VP in the same microdialysate samples of the SON area will also be quantified by immunocapillary electrophoresis with laser-indirect fluorescence detection to examine whether a) IL-1beta infused locally alters dendritic release of OT from magnocellular neurons; b) endogenous release of IL-1beta occurs within the SON area during 1, 3, 5 or 8 days of drinking 2 percent NaCI; and c) OT and IL-1beta release in the SON area in response to drinking 2 percent NaCI is altered by an IL-1 receptor antagonist, inhibitors of prostaglandin synthesis (meclofenamate) and nitric oxide synthase (L-NAME) or by blockers of neuronal conduction (tetrodotoxin, omega conotoxin GVIA and omega-agatoxin IVA). Lastly, we will functionally map (Fos expression; immunohistochemistry) forebrain areas (subfornical organ SFO; organum vasculosum lamina terminalis, OVLT; median preoptic nucleus) that activate the magnocellular system after drinking 2 percent NaCI for 2 or 8 days and determine if intracerebroventricular administration of an IL-1 receptor antagonist alters this response. The proposed research will provide a functional assessment of IL-1beta in the magnocellular system and its neuromodulatory role on the central (intranuclear) and peripheral release of OT (and VP) from the magnocellular neuroendocrine system during chronic stimulation.