IL-6-mediated Jak2/Stat3 signaling and Brain Development

IL-6 介导的 Jak2/Stat3 信号传导与大脑发育

• 批准号: 8135535
• 负责人: Jun Tan
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135535
• 关键词: Adult; Adult Children; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Attenuated; Autistic Disorder; Behavior; Behavioral; Bioflavonoid; Blood; Brain; Cell Nucleus; Cells; Chemicals; Child; Citrus; Clinical Research; Clinical Trials; Data; Defect; Development; Diet; Diosmin; Event; Fetus; Folate; Food; Foundations; Functional disorder; Future; Human; Immune; Immune system; Immunohistochemistry; Impairment; Infection; Inflammatory; Injection of therapeutic agent; Interleukin-6; Lead; Light; Luteolin; Mediating; Molecular; Mothers; Mus; Neural Tube Defects; Neurons; Newborn Infant; Oral; Oral Administration; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Primary Cell Cultures; Problem behavior; Process; Production; Prophylactic treatment; Proteins; Qualifying; Recombinants; Regulation; Reporting; Risk; Role; STAT3 gene; Signal Pathway; Signal Transduction; Social Behavior; Social Interaction; Stat3 protein; Supplementation; Testing; Time; Validation; Vision; Western Blotting; Work; attenuation; behavior test; behavioral impairment; brain tissue; cytokine; fetal; flavanoid; immune activation; improved; in utero; in vivo; inhibitor/antagonist; maternal serum; neurodevelopment; offspring; pregnant; prenatal; public health relevance; therapeutic target; young adult

DESCRIPTION (provided by applicant): It has been suggested that maternal immune activation (MIA) by a range of infections can affect fetal brain development and thus behavior of young and adult offspring. Most recently, Smith and colleagues (2007) reported that increased IL-6 in the maternal serum plays a key role in altering fetal brain development and impairing behaviors in social interactions in the offspring, all the way into adulthood. Interestingly, these effects could be attenuated by blocking IL-6, using anti-IL-6 antibody and/or mice deficient in IL-6. Our preliminary studies showed that the citrus bioflavonoid, luteolin, inhibits neuronal JAK2/STAT3 phosphorylation in both murine neuron-like (N2a) cells and primary cultured neuronal cells challenged with mouse recombinant IL-6 protein. As a validation of these findings, we next examined the effects of a STAT3 inhibitor (S31-201) and diosmin, a flavanoid structurally similar to luteolin, on JAK2/STAT3 signaling in vivo. When either agent was applied to pregnant mice with an injection of IL-6, JAK2/STAT3 phosphorylation and pro-inflammatory cytokines were both significantly reduced in brain homogenates from newborn mice. We further showed that diosmin administered orally in chow [10 mg/kg/day (0.005% diosmin in NIH31 control chow)] significantly changes behavioral deficits in social interaction and reduces pro-inflammatory cytokines in brain tissues of IL-6/MIA adult offspring. We also found that diosmin reduces the CNS levels in pro- inflammatory cytokines consistent with JAK2/STAT3 signal pathway inhibition. It's well known that the risk of altering fetal brain development is associated with prenatal maternal infection, specifically, with cytokine- related inflammatory events in the CNS. Presumably, diosmin molecular inhibition of JAK2/STAT3 pathway could be involved in improving abnormal social interaction in IL-6/MIA adulthood offspring. In this proposal, we will examine whether or not JAK2/STAT3 signal pathway activation could be specifically involved in brain histological abnormalities in IL-6-induced MIA (presumably resulting in development of abnormal behavior in adult offspring that mimics features of autism). In addition, we intend to fully characterize and qualify diosmin's potential effect on improving abnormal, autistic like social behaviors in IL-6/MIA offspring in adulthood via its attenuation of the JAK2/STAT3 signal pathway. These studies could lay the foundation for autism clinical trials with diosmin diet supplementation in the near future. PUBLIC HEALTH RELEVANCE: It has been suggested that activation of pregnant mother's immune system by infections can affect the brain of the developing fetus and thus behavior of young and adult offspring. Most recently, it was reported that increased IL-6 (a chemical messenger of the immune system) in the mother's blood plays a key role in altering fetal brain development and impairing behaviors in social interactions in the offspring. Interestingly, these effects could be avoided by blocking IL-6 chemically with an antibody or by genetically altering mice so they are deficient in IL-6. Our preliminary studies showed that the natural citrus molecule, luteolin, inhibits the signaling mechanism (JAK2/STAT3) in neurons which carries IL-6's signal to the nucleus. This occurred in neuron-like (N2a) cells and neurons removed and cultured from mouse brains and then challenged with mouse IL-6 protein. As a validation of these findings, we next examined the effects of an artificial STAT3 inhibitor and diosmin, a structurally similar natural citrus molecule to luteolin, on JAK2/STAT3 signaling in mice. When either agent was applied to pregnant mice with an injection of IL-6 to activate the mother's immune system JAK2/STAT3 activation and inflammatory cytokines were both significantly reduced in the brains of the newborn mice. We further showed that diosmin given orally mixed in mouse food significantly improves behavioral problems in social interaction and reduces inflammatory cytokines in brain tissues of the offspring of the IL-6 injected mothers. Further, diosmin specifically reduces the brain inflammatory cytokines triggered by JAK2/STAT3 signaling. Presumably, diosmin inhibition of JAK2/STAT3 pathway could be involved in improving abnormal social interaction in offspring of IL-6 injected mothers. In this proposal, we will examine whether or not JAK2/STAT3 signal pathway activation could be specifically involved in brain structural abnormalities in IL-6-induced activation of the maternal immune system (presumably resulting in development of abnormal behavior in adult offspring that mimics features of autism). In addition, we intend to fully test diosmin's potential effect on improving abnormal, autistic like behaviors of offspring of IL-6 immune activated mothers by the JAK2/STAT3 signal pathway blocking with diosmin. These studies could lay the foundation for diosmin as a prenatal supplement in at-risk mothers to avoid autism development in their children, much like folate is currently in use to avoid neural tube defects.

描述（由申请人提供）：已经提出，一系列感染的母体免疫激活（MIA）会影响胎儿脑发育，从而影响年轻和成人后代的行为。最近，Smith及其同事（2007年）报告说，母性血清中的IL-6在改变胎儿脑发育和损害后代社会互动中的行为方面起着关键作用，一直到成年。有趣的是，使用抗IL-6抗体和/或小鼠IL-6中的抗IL-6可以通过阻断IL-6来减弱这些作用。我们的初步研究表明，柑橘类生物黄酮叶黄素蛋白抑制了鼠神经元样细胞（N2A）细胞和原代培养的神经元细胞的神经元JAK2/STAT3磷酸化。作为对这些发现的验证，我们接下来研究了STAT3抑制剂（S31-201）和Diosmin的作用，Diosmin（类似于Luteolin在结构上，类似于Luteolin，对Vivo中的JAK2/STAT3信号传导）的影响。当将任何一种药物用于注射IL-6的怀孕小鼠时，JAK2/STAT3磷酸化和促炎性细胞因子的脑匀浆都显着降低。我们进一步表明，在ChOW [10 mg/kg/day（NIH31对照食物中的0.005％diosmin）中口服的二敏蛋白]显着改变社交相互作用的行为缺陷，并减少IL-6/MIA成人成人后代脑组织中的促炎细胞因子。我们还发现，diosmin降低了与JAK2/STAT3信号途径抑制一致的炎性细胞因子中的CNS水平。众所周知，改变胎儿脑发育的风险与CNS中细胞因子相关的炎症事件特别是产前孕产妇感染有关。据推测，Diosmin分子对JAK2/STAT3途径的抑制可能与改善IL-6/MIA成年后代的社会相互作用有关。 在此提案中，我们将检查JAK2/STAT3信号途径激活是否可以专门参与IL-6诱导的MIA的大脑组织学异常（大概会导致成人后代的异常行为发展，该后代模仿了自闭症特征）。此外，我们打算通过通过对JAK2/STAT3信号途径的衰减来充分表征和鉴定Diosmin对IL-6/MIA后代的社交行为的潜在影响。这些研究可以在不久的将来补充Diosmin饮食，为自闭症临床试验奠定基础。 公共卫生相关性：有人提出，通过感染激活怀孕母亲的免疫系统会影响发育中的胎儿的大脑，从而影响年轻和成人后代的行为。最近，据报道，母亲血液中的IL-6（免疫系统的化学信使）在改变胎儿脑发育和损害后代社会互动中的行为方面起着关键作用。有趣的是，可以通过用抗体化学阻断IL-6或通过遗传改变小鼠来避免这些作用，从而避免使用IL-6。我们的初步研究表明，天然柑橘分子Luteolin抑制神经元中的信号传导机制（JAK2/STAT3），该神经元将IL-6信号带到细胞核中。这发生在从小鼠大脑中去除并培养的神经元样细胞（N2A）细胞中，然后用小鼠IL-6蛋白挑战。作为对这些发现的验证，我们接下来研究了人造STAT3抑制剂和Diosmin的影响，该抑制剂（一种与le luteolin在结构上相似的天然柑橘分子在小鼠中JAK2/STAT3信号传导中的影响。当两种药物被注射到IL-6以激活母亲的免疫系统JAK2/STAT3激活和炎症细胞因子的孕妇小鼠中，新生小鼠的大脑都大大降低了。我们进一步表明，在小鼠食品中口服混合的diosmin显着改善了社交相互作用的行为问题，并减少了IL-6注射母亲的后代的脑组织中的炎症细胞因子。此外，Diosmin专门降低了由JAK2/STAT3信号触发的脑炎症细胞因子。据推测，Diosmin对JAK2/STAT3途径的抑制可能与改善IL-6注射母亲后代的社会互动有关。在该提案中，我们将检查JAK2/STAT3信号途径是否可以专门参与IL-6诱导的母体免疫系统激活中的大脑结构异常（可能导致成人后代的异常行为的发展，该异常是模仿成人的特征自闭症）。此外，我们打算全面测试Diosmin对改善异常，自闭症的潜在影响，例如IL-6免疫激活母亲的后代通过JAK2/STAT3信号途径阻止Diosmin的bother剂量。这些研究可以为diosmin作为高危母亲的产前补充剂奠定基础，以避免儿童的自闭症发展，就像叶酸一样，目前正在使用以避免神经管缺陷。

项目成果

Psychotropic effects of antimicrobials and immune modulation by psychotropics: implications for neuroimmune disorders.

抗菌药物的精神作用和精神药物的免疫调节：对神经免疫性疾病的影响。

• DOI: 10.2217/npy.12.41
• 发表时间: 2012
• 期刊: Neuropsychiatry
• 作者: Obregon,Demian;Parker-Athill,EllisaCarla;Tan,Jun;Murphy,Tanya
• 通讯作者: Murphy,Tanya

Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism.

• DOI: 10.1016/j.jneuroim.2009.08.012
• 发表时间: 2009-12-10
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Parker-Athill E;Luo D;Bailey A;Giunta B;Tian J;Shytle RD;Murphy T;Legradi G;Tan J
• 通讯作者: Tan J