Transciption-independent Signaling by IL1 in Neurons

神经元中 IL1 的转录独立信号传导

• 批准号: 7038982
• 负责人: TAMAS BARTFAI
• 金额: $ 34.82万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038982
• 关键词: biological signal transduction; ceramides; cytokine receptors; electrophysiology; enzyme activity; gel electrophoresis; hypothalamic pituitary axis; hypothalamus; interleukin 1; laboratory mouse; mitogen activated protein kinase; neurons; nuclear factor kappa beta; phosphodiesterases; phosphorylation; polymerase chain reaction; pyrogens; second messengers; sphingomyelin phosphodiesterase; thin layer chromatography; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The pro-inflammatory cytokine interleukin 1-Beta (IL-1Beta) suppresses the activity of warm sensitive neurons in the hypothalamus in vivo and in vitro, and this action appears to underlie its activity as a pyrogen (fever-inducing agent). The suppression occurs within 100-300 milliseconds after application of IL-1Beta, and the signaling mechanisms are not known. The speed of the effects suggest that NFKB mediated transcriptional changes, which are the most studied signaling pathways for IL-1Beta action, are not likely to be responsible for this rapid action of IL-1Beta. The goal of this study is to identify the molecular mechanisms of rapid IL-1Beta signaling, using thermosensitive hypothalamic neurons as a model. We will use biochemical and molecular biological, cellular, electrophysiological, and in vivo telemetrical approaches to identify the second messenger system involved in the rapid IL-1Beta effects on hypothalamic warm-sensitive neurons, and subsequently on the fever response. We have preliminary data indicating that IL-1Beta stimulation of sphingomyelinase activity through the type 1 IL-1 receptor may be involved in the rapid signaling of IL-1Beta. The cell penetrating analog of the sphingomyelinase product C2 ceramide causes rapid fever response reminiscent of the early phase of IL-1Beta induced fever. In vitro C2 ceramide activates phosphorylation of ERK in hypothalamic neurons similar to IL-1Beta. We will test the hypothesis that rapid effects of IL-1Beta involve ceramide-mediated protein phosphorylation-dependent changes in neuronal activity and that ceramide acts as second messenger of the rapid non-transcription dependent actions of IL-1Beta. Since IL-1 receptors are constitutively expressed in the hypothalamus, defining their molecular mechanisms of action will contribute to a better understanding of the neuronal effects of IL-1Beta in the hypothalamus, where it regulates the HPA axis, the temperature setpoint, and fever response

描述（由申请人提供）：促炎性细胞因子白介素1-β（IL-1BETA）抑制了体内和体外下丘脑中温暖敏感的神经元的活性，并且这种作用似乎是其作为Pyrogen（发烧剂）的活性。抑制在应用IL-1Beta后发生在100-300毫秒内，信号传导机制尚不清楚。效果的速度表明，NFKB介导的转录变化是IL-1Beta作用的最多研究的信号通路，不太可能对IL-1Beta的这种快速作用负责。这项研究的目的是使用热敏感下丘脑神经元作为模型来确定快速IL-1BETA信号传导的分子机制。我们将使用生化和分子生物学，细胞，电生理和体内远程学方法来鉴定与下丘脑温暖敏感神经元快速影响有关的第二个允许系统，以及随后对发烧反应。我们有初步数据，表明通过1型IL-1受体对鞘磷脂酶活性的刺激可能参与IL-1Beta的快速信号传导。鞘磷脂酶产物的细胞穿透类似物C2神经酰胺会引起快速发烧反应，让人联想到IL-1Beta诱导的发烧的早期阶段。体外C2神经酰胺激活下丘脑神经元中类似IL-1Beta的ERK的磷酸化。我们将检验以下假设：IL-1Beta的快速作用涉及神经酰胺介导的蛋白质磷酸化依赖性神经元活性的变化，并且神经酰胺充当IL-1Beta快速非转录依赖性作用的第二信使。由于IL-1受体在下丘脑中组成型表达，因此定义其分子机制将有助于更好地理解下丘脑IL-1Beta的神经元作用，在此调节HPA轴，温度设定值和发烧响应响应

项目成果

Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity.

• DOI: 10.1016/j.cyto.2008.07.004
• 发表时间: 2008-10
• 期刊: CYTOKINE
• 影响因子: 3.8
• 作者: Osborn, O.;Brownell, S. E.;Sanchez-Alavez, M.;Salomon, D.;Gram, H.;Bartfai, T.
• 通讯作者: Bartfai, T.

Prostaglandin E2-increased thermosensitivity of anterior hypothalamic neurons is associated with depressed inhibition.

• DOI: 10.1073/pnas.0308718101
• 发表时间: 2004-02
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: I. Tabarean;M. Behrens;T. Bártfai;H. Korn

Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice.

• DOI: 10.1016/j.bbi.2013.12.001
• 发表时间: 2014-03
• 期刊: BRAIN BEHAVIOR AND IMMUNITY
• 影响因子: 15.1
• 作者: Zorrilla, Eric P.;Conti, Bruno
• 通讯作者: Conti, Bruno

Ccl22/MDC, is a prostaglandin dependent pyrogen, acting in the anterior hypothalamus to induce hyperthermia via activation of brown adipose tissue.

• DOI: 10.1016/j.cyto.2010.11.017
• 发表时间: 2011-03
• 期刊: CYTOKINE
• 影响因子: 3.8
• 作者: Osborn, Olivia;Sanchez-Alavez, Manuel;Dubins, Jeffrey S.;Gonzalez, Alejandro Sanchez;Morrison, Brad;Hadcock, John R.;Bartfai, Tamas
• 通讯作者: Bartfai, Tamas