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

• 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
• 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

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质。这些因素对于调节免疫和炎症反应，调节淋巴发育和分化尤为重要。 细胞因子还调节免疫稳态，耐受性和记忆力。毫不奇怪，细胞因子在自身免疫性疾病（例如类风湿关节炎，全身性红斑狼疮，炎症性肠病和牛皮癣）的发病机理中至关重要。 了解细胞因子作用的分子基础为免疫介导疾病的发病机理提供了重要的见解，并提供了新的治疗靶标。 细胞因子受体与Janus家族激酶（JAKS）有关，该激酶启动信号（请参阅Project AR041106-14）。 激活JAKS后，信号传导的下一步是激活称为统计数据的转录因子（信号换能器和转录激活因子）（请参阅Project 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T细胞进行了转录分析。 我们确定了大量诱导基因，其中一些基因以前被认为是IL-12诱导的。这样的基因是编码丝氨酸/苏氨酸激酶COT/TPL2的基因。该激酶被IL-12直接诱导，并被IL-4抑制。 随着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是直接的STAT4靶标。为了定义MAP3K8的作用，我们研究了MAP3K8敲除小鼠。 我们发现MAP3K8 - / - 小鼠的thelper1分化显着缺陷。 我们进一步发现，这与未能上调转录因子STAT4和TBOX21（T-BET）有关，从而解释了无法正确生成IFNG的失败。 用弓形虫弓形虫对MAP3K8缺陷小鼠的挑战表明，这些小鼠对该模型病原体的敏感性增加，这与产生IFNG的能力受损一致。 相反，在模仿多发性硬化症，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-敲除小鼠的严重程度降低了。 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。 还确定了T细胞表达的MAP3K8在炎症性肠病模型中的重要性。