Cytokines and Hypothalamic-Pituitary-Immune Interactions

描述（由申请人提供）：本提案的长期目标是了解免疫和神经内分泌系统在被炎症刺激激活时如何相互作用。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，以及瘦素和黑皮质素系统对炎症的细胞因子和HPA反应的调节。有证据表明，瘦素，这是由脂肪细胞合成的，并在调节能量平衡中起着关键作用，也可以调节炎症反应。α-MSH来源于前阿黑皮素（POMC）前体蛋白，在外周合成，并可由瘦素调节。α-MSH具有有效的抗炎特性，并且可以拮抗炎性细胞因子的许多作用。然而，关于内源性黑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，所述内源性黑皮质素系统由α-MSH、黑皮质素受体和MSH拮抗剂、刺鼠相关蛋白（AGRP）组成。该提案将检查瘦素、α-MSH和AGRP在调节恒河猴中促炎细胞因子（IL-1-β、IL-6、TNF-α）和抗炎细胞因子（IL-1-β和IL-10）对内毒素和IL-1-β的反应中的作用。主要目标是确定α-MSH和AGRP在调节HPA对炎症刺激的反应中中枢和外周发挥的生理作用，并确定瘦素对HPA轴的影响是否部分由α-MSH介导。啮齿动物模型将用于检查内毒素对下丘脑中POMC和AGRP基因表达的影响，并检查瘦素对IL-1-β刺激的CRH从下丘脑体外释放的影响。过表达α-MSH和聚集蛋白的小鼠也将用于研究黑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。炎性细胞因子与从感染性和自身免疫性疾病到骨质疏松症和心血管疾病的广泛的人类疾病有关。在大脑中，炎症细胞因子与神经退行性疾病和疾病相关的抑郁症有关。因此，了解调节这种炎性细胞因子级联反应的内源性激素机制与广泛的人类疾病有关

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