LIF MEDIATES ACTH AXIS RESPONSE TO INFLAMMATION

LIF 介导 ACTH 轴对炎症的反应

• 批准号: 6150655
• 负责人: VERA M CHESNOKOVA
• 金额: $ 11.23万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-10 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150655
• 关键词: adrenocorticotropic hormone; corticosterone; corticotropin releasing factor; endotoxins; experimental allergic encephalomyelitis; gene expression; gene targeting; genetically modified animals; hypothalamic pituitary adrenal axis; inflammation; laboratory mouse; leukemia inhibitory factor; lipopolysaccharides; neuroendocrine system; neuroimmunomodulation; proopiomelanocortin; stress; systemic lupus erythematosus

The hypothalamo-pituitary-adrenal axis (HPA) plays an important role in the relationship between the immune and neuroendocrine systems. Blunting of the HPA response to stress enhances susceptibility to or severity of inflammatory/autoimmune disease. The cascade of HPA hormones released under stress conditions may exert a dampening role on specific defense mechanisms, especially on most cellular actions of the inflammatory immune response. Cytokines, polypeptide mediators, classically associated with immune system regulation and inflammation, play a significant role in the HPA axis activation during immune disorders and actively mediate signaling between the immune and endocrine systems. Leukemia inhibitory factor (LIF), a pleotropic cytokine with diverse biologic activities, also present in pituitary corticotrophs, stimulates proopiomelanocortin (POMC) gene transcription, and is significantly induced in mouse hypothalamus and pituitary in response to endotoxin. As LIF is an inducible proinflammatory hypothalamo-pituitary cytokine which may function as a paracrine regulator of ACTH we hypothesize that LIF is involved in control of the inflammatory/autoimmune process acting through regulation of the HPA axis. Preliminary studies conducted in LIF knockout mice, and shown herein, demonstrate that in the absence of LIF, mice cannot maintain an appropriate level of HPA axis activation in response to stress and exogenous IL 1. In addition, the low HPA response to mycobacterial adjuvant observed in knockout animals compared to normal littermates shows a strong correlation between LIF-regulated activity of the HPA axis and susceptibility to inflammatory process. In this study we will determine the molecular and physiological mechanisms implicating LIF in the neuroendocrine control of inflammation. We will utilize both in vivo whole animal models as well as in vitro molecular techniques to characterize the role of LIF in mediating HPA axis response to pathological stress. The hypothesis that LIF mediates the HPA axis response to acute inflammatory challenges as well as to experimental (experimental allergic encephalomyelitis) and genetically determined (systemic lupus erythematosus) inflammatory/autoimmune disease will be tested. This study will provide insights into the cytokine-mediated neuro-immuno-endocrine interface.

下丘脑 - 垂体 - 肾上腺轴（HPA）在 免疫和神经内分泌系统之间的关系。 HPA对压力的反应的钝化增强了对OR的敏感性 炎症/自身免疫性疾病的严重程度。 HPA激素的级联 在压力条件下释放可能会在特定上发挥抑郁症作用 防御机制，特别是在大多数细胞动作上 炎症免疫反应。细胞因子，多肽介质， 与免疫系统调节和炎症相关， 免疫期间在HPA轴激活中起重要作用 疾病并积极介导免疫和 内分泌系统。 白血病抑制因子（LIF），一种胸膜 具有不同生物学活性的细胞因子，也存在于垂体中 皮质营养，刺激促蛋白酶皮质素（POMC）基因转录， 并在小鼠下丘脑和垂体中显着诱导 对内毒素的反应。 因为LIF是一种可诱导的促炎 下丘脑 - 垂体细胞因子可能起旁分泌的作用 ACTH的调节剂我们假设LIF参与控制 通过调节HPA起作用的炎症/自身免疫过程 轴。 在LIF基因敲除小鼠中进行的初步研究，并显示 在此证明，在没有LIF的情况下，小鼠无法保持 适当水平的HPA轴激活应对压力和 外源IL 1。此外，HPA对分枝杆菌的反应低 与普通同窝仔相比，在基因敲除动物中观察到的佐剂 显示了HPA的LIF调节活性之间的密切相关性 轴和对炎症过程的敏感性。 在这项研究中，我们将 确定涉及LIF的分子和生理机制 神经内分泌的炎症控制。 我们将两者都在 整个动物模型以及体外分子技术 表征LIF在介导HPA轴响应中的作用 病理压力。 LIF介导HPA轴的假设 对急性炎症挑战以及实验的反应 （实验性过敏性脑脊髓炎）和遗传确定的 （全身性红斑狼疮）炎症/自身免疫性疾病将是 测试。 这项研究将提供有关细胞因子介导的见解 神经免疫 - 内分泌界面。