MAP3K8 in immunoregluation, host defense and autoimmunity

细胞因子是调节细胞生长和分化的分泌蛋白质。这些因子在调节免疫和炎症反应、调节淋巴样细胞的发育和分化方面尤为重要。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起着关键作用。了解细胞因子作用的分子基础有助于深入了解免疫介导性疾病的发病机制，并提供新的治疗靶点。 细胞因子受体与Janus家族激酶(JAKs)相关，后者启动信号传递(见AR041106-14项目)。在JAKs激活后，信号传递的下一步是激活一系列称为STAT(信号转导和转录激活子)的转录因子(见AR041159-01项目)。 为了更好地了解细胞因子的分子作用，我们对白介素12激活的小鼠和人T细胞进行了转录图谱分析。我们鉴定了大量的诱导基因，其中一些以前被认为是IL-12诱导的。其中一个这样的基因是编码丝氨酸/苏氨酸激酶Cot/Tpl2的基因。该激酶可被IL-12直接诱导，但被IL-4抑制。由于IL-12激活了转录因子STAT4，我们还评估了STAT4缺陷小鼠可诱导的MAP3K8表达的依赖性。此外，通过染色质免疫沉淀，我们发现MAP3K8是STAT4的直接靶标。为了确定MAP3K8的作用，我们研究了MAP3K8基因敲除小鼠。我们发现MAP3K8-/-小鼠Therper1分化明显不足。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产生IFNG。用弓形虫攻击MAP3K8基因缺陷小鼠表明，这些小鼠对这种模型病原体的敏感性增加，这与产生IFNG的能力受损是一致的。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基因敲除小鼠的疾病严重程度降低。由于EAE是一种典型的IL-17驱动的疾病，我们正在研究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被证实。 我们还研究了MAP3K8在先天免疫细胞中的作用。我们发现，在树突状细胞(DC)中，MAP3K8在Toll样受体(TLR)信号转导中起关键作用。有趣的是，MAP3K8的缺失严重损害了TLR依赖的IL-1的产生。因此，缺乏MAP3K8的小鼠对单核细胞增多性李斯特菌感染高度敏感。

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 are 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. We also investigated the role of MAP3K8 in innate immune cells. We found that in dendritic cells (DC), MAP3K8 was critical for Toll-like receptor (TLR) signaling. Interestingly, absence of MAP3K8 profoundly impaired TLR-dependent IL-1 production. Consequently, mice lacking MAP3K8 were highly susceptible to infection with Listeria monocytogenes.