Interleukin and the Magnocellular Neuroendocrine System

描述(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做出反应。然而，新的证据表明，在中枢神经系统内，有内在的神经系统表达白介素1β(IL-1β)。在大细胞神经内分泌系统中，IL-1β存在于分泌颗粒中，与催产素(OT)和加压素(VP)分离，是独立释放的标志。这种细胞因子可能会在慢性刺激期间通过饮用高渗盐水(2%NaCI)和哺乳来调节神经垂体激素的分泌，因为这三种多肽都会从神经叶中耗尽。本研究旨在了解IL-1β在大细胞系统中的神经生物学作用，以及它与前列腺素和一氧化氮(NO)在调节大细胞神经元胞体和树突及其神经叶轴突终末释放OT中的相互作用。用免疫亲和毛细管电泳法和激光诱导荧光检测法，对饮用2%NaCI 1、3、5、8天的动物和哺乳期2、5、10、15、21天的断奶大鼠血浆IL-1β、OT和VP与视上核(SON)和神经叶含量之间的定量关系进行了研究。同时，用免疫毛细管电泳法结合激光间接荧光检测检测SON区微透析液标本中IL-1β、OT和VP的含量，以观察局部输注IL-1β是否改变大细胞神经元树突状释放OT：b)饮用2%NaCI后1、3、5或8天，SON区出现内源性IL-1β释放；C)IL-1受体拮抗剂、前列腺素合成抑制剂(甲氯芬酸酯)和一氧化氮合酶(L-NAME)或神经元传导阻断剂(河豚毒素、欧米茄毒素GVIA和欧米茄毒素IVA)可改变SON区对饮用2%NaCI的反应释放的OT和IL-1β。最后，我们将功能性地定位(Fos表达；免疫组织化学)前脑区域(穹隆下器官SFO；终板血管器，OVLT；正中视前核)，这些区域在饮用2%NaCI 2或8天后激活大细胞系统，并确定脑室内注射IL-1受体拮抗剂是否改变这一反应。这项拟议的研究将提供大细胞系统中IL-1β的功能评估，以及在慢性刺激过程中，IL-1β对大细胞神经内分泌系统的中枢(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.