Cytokines and Hypothalamic-Pituitary-Immune Interactions

描述(申请人提供)：这项建议的长期目标是了解免疫和神经内分泌系统在炎症刺激激活时是如何相互作用的。具体目标将集中在炎症细胞因子和下丘脑-垂体-肾上腺(HPA)激活的机制，以及瘦素和黑素皮质素系统对细胞因子和HPA炎症反应的调节。有证据表明，瘦素是由脂肪细胞合成的，在调节能量平衡方面起着关键作用，它也可以调节炎症反应。α-MSH来源于前阿片黑素皮质素(POMC)前体蛋白，在外周合成，可受瘦素调节。α-MSH具有强大的抗炎特性，可以拮抗炎症细胞因子的许多作用。然而，对内源性黑素皮质素系统在调节细胞因子和神经内分泌反应中的作用知之甚少，该系统由黑素皮质素受体α-MSH和MSH拮抗剂刺鼠相关蛋白(AGRP)组成。本研究将研究瘦素、α-MSH和AGRP在调节恒河猴对内毒素和IL-1-β的促炎反应(IL-1-β、IL-6、TNF-α)和抗炎细胞因子(1L-1-β和IL-10)中的作用。主要目标将是确定α-MSH和AGRP在调节HPA对炎症刺激的反应中所起的中枢和外周生理作用，以及确定瘦素对HPA轴的影响是否部分由α-MSH介导。采用啮齿动物模型，观察内毒素对下丘脑POMC和AGRP基因表达的影响，以及瘦素对IL-1-β刺激下丘脑释放CRH的影响。过度表达α-MSH和刺鼠蛋白的小鼠也将被用于研究黑素皮质素系统和瘦素在调节细胞因子和神经内分泌对内毒素的反应中的作用。炎症细胞因子与多种人类疾病有关，从传染病和自身免疫性疾病到骨质疏松症和心血管疾病。在大脑内，炎性细胞因子与神经退行性疾病和疾病相关性抑郁症有关。因此，了解调节炎性细胞因子级联反应的内源性激素机制与多种人类疾病有关。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how the immune and neuroendocrine systems interact when activated by an inflammatory stimulus. The Specific Aims will focus on the inflammatory cytokines and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation, and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system. There is evidence that leptin, which is synthesized by fat cells and plays a key role in regulating energy homeostasis, can also modulate the inflammatory response. Alpha-MSH which is derived from the proopiomelanocortin (POMC) precursor protein, is synthesized in the periphery and can be regulated by leptin. Alpha-MSH has potent anti-inflammatory properties and can antagonize many of the actions of the inflammatory cytokines. Little is known, however, about the role of the endogenous melanocortin system, consisting of alpha-MSH, the melanocortin receptors, and the MSH antagonist, agouti-related protein (AGRP), in modulating cytokine and neuroendocrine responses. This proposal will examine the role of leptin, alpha-MSH and AGRP in modulating pro-inflammatory (IL-1-beta, IL-6, TNF-alpha) and anti-inflammatory cytokine (1L-1-beta and IL-10) responses to endotoxin and IL-1-beta in the rhesus monkey. Major goals will be to determine the physiological roles that alpha-MSH and AGRP play both centrally and peripherally in modulating the HPA response to an inflammatory challenge and to determine if the effects of leptin on the HPA axis are mediated in part by alpha-MSH. A rodent model will be used to examine the effects of endotoxin on POMC and AGRP gene expression in the hypothalamus and to examine the effects of leptin on IL-1-beta stimulated CRH release from the hypothalamus in vitro. Mice which overexpress alpha-MSH and agouti protein will also be utilized to study the role of the melanocortin system and of leptin in modulating cytokine and neuroendocrine responses to endotoxin. Inflammatory cytokines have been implicated in a wide spectrum of human diseases ranging from infectious and autoimmune diseases to osteoporosis and cardiovascular disease. Within the brain, inflammatory cytokines have been implicated in neurodegenerative disease and illness-associated depression. An understanding of the endogenous hormonal mechanisms which regulate this inflammatory cytokine cascade is thus relevant to a broad range of human diseases