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、调节淋巴发育和分化中特别重要。 细胞因子还调节免疫稳态、耐受性和记忆。毫不奇怪，细胞因子在自身免疫性疾病如类风湿性关节炎、系统性红斑狼疮、炎症性肠病和银屑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（见项目AR 041106 -14）。 在激活Jaks之后，信号传导的下一步是激活一个称为Stats（转录的信号转导子和激活子）的转录因子家族（见项目AR 041159 -01）。 为了更好地理解细胞因子的分子作用，我们对白细胞介素（IL）-12激活的小鼠和人T细胞进行了转录谱分析。 我们确定了大量的诱导型基因，其中一些以前被认为是IL-12诱导。一种这样的基因是编码丝氨酸/苏氨酸激酶Cot/Tpl 2的基因。该激酶可被IL-12直接诱导并被IL-4抑制。 由于IL-12激活转录因子Stat 4，我们还评估了Stat 4缺陷小鼠中诱导型MAP 3 K8表达的依赖性。 此外，使用染色质免疫沉淀，我们发现MAP 3 K8是Stat 4的直接靶标。为了确定MAP 3 K8的作用，我们研究了MAP 3 K8敲除小鼠。 我们发现MAP 3 K8-/-小鼠的Thelper 1分化明显缺陷。 我们进一步发现，这与未能上调转录因子Stat 4和Tbox 21（T-bet）有关，从而解释了未能正确产生IFNg。 用弓形虫攻击MAP 3 K8缺陷小鼠显示，这些小鼠对该模型病原体的易感性增加，与产生IFNg的能力受损一致。 相反，在模拟多发性硬化、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，MAP 3 K8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，我们正在研究MAP 3 K8在Th 17细胞和Treg细胞分化中的作用。 T细胞表达的MAP 3 K8在炎症性肠病模型中的重要性也正在确定中。 我们还研究了MAP 3 K8在先天免疫细胞中的作用。 我们发现在树突状细胞（DC）中，MAP 3 K8对Toll样受体（TLR）信号传导至关重要。 有趣的是，MAP 3 K8的缺乏严重损害了TLR依赖性IL-1的产生。 因此，缺乏MAP 3 K8的小鼠对单核细胞增生李斯特菌感染高度易感。

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.