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: 7985709
• 负责人: Jun Tan
• 金额: $ 22.05万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985709
• 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; Figs - dietary; Folate; Food; Foundations; Functional disorder; Future; Human; Immune; Immune system; Immunohistochemistry; Impairment; Infection; Inflammatory; Injection of therapeutic agent; Interleukin-6; JAK2 gene; Janus kinase 2; Lead; Light; Luteolin; Mediating; Molecular; Mothers; Mus; Neural Tube Defects; Neurons; Newborn Infant; Oral; Oral Administration; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Primary Cell Cultures; Principal Investigator; Problem behavior; Process; Production; Prophylactic treatment; Proteins; Qualifying; Recombinants; Regulation; Reporting; Risk; Role; 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; programs; 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(申请人提供)：已经表明，母体免疫激活(MIA)的一系列感染可以影响胎儿的大脑发育，从而影响年轻和成年后代的行为。最近，Smith和他的同事(2007)报告说，母亲血清中IL-6的增加在改变胎儿大脑发育和损害后代的社交行为方面发挥了关键作用，一直到成年。有趣的是，这些影响可以通过阻断IL-6、使用抗IL-6抗体和/或缺乏IL-6的小鼠来减弱。我们的初步研究表明，柑橘生物黄酮类化合物木犀草素抑制小鼠神经元样细胞(N2a)和原代培养的神经元细胞在小鼠重组IL-6蛋白刺激下的JAK2/STAT3磷酸化。作为对这些发现的验证，我们接下来检查了STAT3抑制剂(S31-201)和Diosmin(一种结构上类似于木犀草素的黄烷类化合物)在体内对JAK2/STAT3信号的影响。当两种药物中的任何一种应用于注射IL-6的怀孕小鼠时，新生小鼠脑匀浆中JAK2/STAT3的磷酸化和促炎细胞因子都显著减少。我们进一步表明，在日粮中口服地奥明[10 mg/kg/天(0.005%地奥司明在对照日粮中)]显著改变了社会交往中的行为缺陷，并减少了IL-6/MIA成年子代脑组织中的促炎细胞因子。我们还发现，Diosmin降低了促炎症细胞因子中的CNS水平，这与JAK2/STAT3信号通路的抑制一致。众所周知，改变胎儿大脑发育的风险与产前母体感染有关，特别是与中枢神经系统细胞因子相关的炎症事件有关。推测Diosmin分子抑制JAK2/STAT3通路可能参与改善IL-6/MIA成年期子代的异常社会相互作用。在这项研究中，我们将研究JAK2/STAT3信号通路激活是否特异性地参与了IL-6诱导的MIA的脑组织学异常(可能导致成年后代出现模仿自闭症特征的异常行为)。此外，我们打算充分描述和鉴定Diosmin通过减弱JAK2/STAT3信号通路，在成年后改善IL-6/MIA后代异常、自闭症样社会行为的潜在作用。这些研究可能为在不久的将来使用Diosmin饮食补充剂进行自闭症临床试验奠定基础。 与公共卫生相关：有研究表明，感染激活孕妇的免疫系统会影响发育中胎儿的大脑，从而影响幼年和成年后代的行为。最近，有报道称，母亲血液中IL-6(免疫系统的一种化学信使)增加，在改变胎儿大脑发育和损害后代社交行为方面发挥了关键作用。有趣的是，这些影响可以通过用抗体化学阻断IL-6或通过基因改变小鼠使它们缺乏IL-6来避免。我们的初步研究表明，天然柑橘分子木犀草素抑制了神经元中将IL-6‘S信号传递到细胞核的信号机制(JAK2/STAT3)。这发生在神经元样(N2a)细胞和神经元中，从小鼠脑中取出并培养，然后用小鼠IL-6蛋白攻击。作为对这些发现的验证，我们接下来检查了人工STAT3抑制剂和Diosmin对小鼠JAK2/STAT3信号转导的影响。Diosmin是一种结构类似于木犀草素的天然柑橘分子。当将任何一种药物应用于注射IL-6以激活母亲免疫系统的怀孕小鼠时，新生小鼠大脑中JAK2/STAT3的激活和炎性细胞因子都显着减少。我们进一步表明，口服混合了小鼠食物的地奥明显著改善了社交中的行为问题，并减少了注射IL-6的母亲后代脑组织中的炎性细胞因子。此外，Diosmin专门减少JAK2/STAT3信号触发的脑炎性细胞因子。推测Diosmin对JAK2/STAT3通路的抑制可能参与改善注射IL-6母亲的后代的异常社会交往。在这项建议中，我们将研究JAK2/STAT3信号通路的激活是否特定地参与了IL-6诱导的母体免疫系统激活(可能导致成年后代出现模仿自闭症特征的异常行为)的脑结构异常。此外，我们打算充分测试Diosmin通过用Diosmin阻断JAK2/STAT3信号通路来改善IL-6免疫激活母亲的后代异常的自闭症样行为的潜在作用。这些研究可能为地奥司明作为高危母亲的产前补充剂奠定基础，以避免其孩子患自闭症，就像目前使用叶酸来避免神经管缺陷一样。