MAP3K8 in immunoregluation, host defense and autoimmunity

MAP3K8 在免疫调节、宿主防御和自身免疫中的作用

基本信息

批准号：
7732827
负责人：
John O'Shea
金额：
$ 26.03万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732827
关键词：
Autoimmune Diseases Autoimmunity Boxing Cell Differentiation process Cells Cytokine Receptors Dependence Development Disease Experimental Autoimmune Encephalomyelitis Failure Family Genes Goals Homeostasis Host Defense Human Immune Infection Inflammatory Bowel Diseases Inflammatory Response Interferon Type II Interleukin-12 Interleukin-17 Interleukin-4 Knockout Mice Lymphoid MAP3K8 gene Mediating Memory Modeling Molecular Multiple Sclerosis Mus Numbers Pathogenesis Phosphotransferases Predisposition Production Protein-Serine-Threonine Kinases Proteins Psoriasis Rheumatoid Arthritis Role STAT protein STAT4 protein Severity of illness Signal Transduction Systemic Lupus Erythematosus T-Lymphocyte Toxoplasma gondii activating transcription factor base cell growth chromatin immunoprecipitation cytokine human MAP3K8 protein immunoregulation insight novel therapeutics pathogen therapeutic target transcription factor

项目摘要

Cytokines are secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, regulating lymphoid development and differentiation. Cytokines also regulate immune homeostasis, tolerance, and memory. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. Cytokine receptors are associated with Janus family kinases (Jaks), which initiate signaling (see project AR041106-14). Following activation of Jaks, the next step in signaling is the activation of a family of transcription factors called Stats (signal transducers and activators of transcription) (see project AR041159-01). To better understand the molecular actions of cytokines, we performed transcriptional profiling of mouse and human T cells activated by interleukin (IL)-12. We identified a large number of inducible genes, some of which had been previously recognized as being IL-12-inducible. One such gene was the gene encoding the serine/threonine kinase Cot/Tpl2. This kinase was directly inducible by IL-12 and inhibited by IL-4. As IL-12 activates the transcription factor Stat4, we also assessed the dependence of inducible MAP3K8 expression in Stat4-deficient mice. Furthermore, using chromatin immunoprecipitation, we found that MAP3K8 was a direct Stat4 target. To define the role of MAP3K8, we studied MAP3K8 knockout mice. We found that Thelper1 differentiation of MAP3K8-/- mice was markedly deficient. We further found that this was associated with failure to upregulate the transcription factors Stat4 and Tbox21 (T-bet), thus explaining the failure to properly generate IFNg. Challenge of MAP3K8-deficient mice with Toxoplasma gondii showed that these mice had increased susceptibility to this model pathogen, consistent with the impaired ability to generate IFNg. Conversely, in the model of autoimmune disease that mimics multiple sclerosis, experimental autoimmune encephalomyelitis or EAE, MAP3K8-knockout mice had reduced severity of disease. Because EAE is a prototypic IL-17-driven disease, we investigating the role of MAP3K8 in Th17 cell and Treg cell differentiation. The importance of T cell-expressed MAP3K8 in models of inflammatory bowel disease is also being ascertained.

细胞因子是调节细胞生长和分化的分泌蛋白。这些因子对于调节免疫和炎症反应、调节淋巴系统的发育和分化尤其重要。细胞因子还调节免疫稳态、耐受性和记忆。毫不奇怪，细胞因子在类风湿性关节炎、系统性红斑狼疮、炎症性肠病和牛皮癣等自身免疫性疾病的发病机制中至关重要。了解细胞因子作用的分子基础为了解免疫介导疾病的发病机制提供了重要的见解，并提供了新的治疗靶点。细胞因子受体与 Janus 家族激酶 (Jaks) 相关，后者启动信号传导（参见项目 AR041106-14）。 Jaks 激活后，信号传导的下一步是激活称为 Stats（信号转导子和转录激活子）的转录因子家族（参见项目 AR041159-01）。为了更好地了解细胞因子的分子作用，我们对白介素 (IL)-12 激活的小鼠和人类 T 细胞进行了转录分析。我们鉴定出大量诱导基因，其中一些先前已被认为是 IL-12 诱导基因。其中一种基因是编码丝氨酸/苏氨酸激酶Cot/Tpl2的基因。该激酶可直接被 IL-12 诱导并被 IL-4 抑制。由于 IL-12 激活转录因子 Stat4，我们还评估了 Stat4 缺陷小鼠中诱导型 MAP3K8 表达的依赖性。此外，使用染色质免疫沉淀，我们发现 MAP3K8 是 Stat4 的直接靶点。为了明确 MAP3K8 的作用，我们研究了 MAP3K8 敲除小鼠。我们发现 MAP3K8-/- 小鼠的 Thelper1 分化明显缺陷。我们进一步发现这与未能上调转录因子 Stat4 和 Tbox21 (T-bet) 有关，从而解释了未能正确生成 IFNg。用弓形虫攻击 MAP3K8 缺陷小鼠表明，这些小鼠对这种模型病原体的易感性增加，这与产生 IFNg 的能力受损一致。相反，在模拟多发性硬化症、实验性自身免疫性脑脊髓炎或 EAE 的自身免疫性疾病模型中，MAP3K8 敲除小鼠的疾病严重程度降低。由于 EAE 是一种原型 IL-17 驱动的疾病，因此我们研究了 MAP3K8 在 Th17 细胞和 Treg 细胞分化中的作用。 T 细胞表达的 MAP3K8 在炎症性肠病模型中的重要性也正在确定。