Interleukin 4

总结 白细胞介素-4是一种原型I型细胞因子，是过敏性炎症反应的中心调节因子。它控制初始CD 4 T细胞向TH 2表型的极化和IG类向IgE的转换。细胞因子生物学单元已经表征了IL-4受体所利用的信号传导机制。已经表明，潜在转录因子Stat 6的激活控制TH 2极化和IgE类别转换。 该单位的科学家已经确定，GATA 3和Stat 5对于获得IL-4产生能力至关重要。 他们最近进行了全基因组分析组蛋白修饰和转录因子结合在每一个不同的Th谱系，以深入了解Th分化的过程。他们在基因组中与主调节转录因子GATA 3结合的位点的研究方面取得了很好的进展。 这一信息加上STAT 5结合位点的知识，有望为Th 2分化的遗传调控提供重要的见解。 对其他Th细胞系的比较研究应该为这些细胞的分化提供类似的信息。 单位科学家现在已经表明，T细胞受体介导的erk信号通路的激活通过阻止GATA 3的转录和使IL-2受体脱敏来阻断Th 2分化。 强的TCR介导的信号刺激erk磷酸化，从而阻止Th 2分化并导致高抗原浓度下Th 2分化不良。低浓度的抗原仅微弱地激活erk，允许早期IL-4产生和TH 2分化。 研究小组的科学家们还表明，Notch信号通路参与了Th 2细胞的活化，但它不是通过调节GATA 3来实现的，而不是通过调节IL-2的产生。 有限的IL-2，通过限制STAT 5，减少Th 2启动。 通过添加IL-2可以挽救Notch途径缺陷的小鼠中Th 2引发的缺陷。 Gfi-1在其作为转录阻遏物的作用中对于IL-2的稳健生长是关键的，因为它似乎抑制IL-2介导的生长的基因如SOCS 1和SOCS 3的表达。 另一方面，Gfi-1减少响应IL-7的生长，因为它介导TCR和精氨酸介导的IL-7 Ra链的下调。这些研究利用该单位开发的Gfi-1条件性敲除小鼠，确定Gfi-1在淋巴细胞稳态中起关键作用，并且Gfi-1表达的精确调节对于CD 4和CD 8 T细胞的平衡群体至关重要。 此外，Gfi-1在由病毒感染诱导的记忆性CD 4和CD 8细胞的表型中起核心作用。 最近，已经显示Gfi-1抑制向IL-17和T%reg命运的分化。 事实上，Gfi-1似乎作为替代Th 2的命运的阻遏物起作用。 最近，Unit科学家开始分析IL-1家族成员在调节T细胞功能中的作用。 他们已经表明，IL-1是一种有效的增强剂，直接作用于响应抗原的细胞扩增的响应性CD 4 T细胞。 将IL-1添加到免疫方案中可以将T细胞扩增增强多达10倍，并且显著增强对Th 17细胞的引发，并且在较小程度上增强对Th 2细胞的引发。 Uni的科学家还表明，分化的Th效应细胞可以通过IL-1家族成员的刺激和STAT激活来刺激分泌关键细胞因子。 对于Th 1细胞，所需的IL-1家族成员是IL-18，STAT是STAT 4;对于Th 2，IL-33和STAT 5，对于Th 17，IL-1和STAT 3。 此外，深入了解用于IL-4和IL-13反应的独特信号传导机制，重点是I型和II型IL-4受体的不同作用以及不同细胞类型对这些同源物的相对敏感性如何不同。为此，已详细分析了野生型和γ共同缺陷小鼠的各种巨噬细胞群体对IL-4和IL-13的反应。 已经评估了通过辉光细胞计数分析测量的STAT 6的磷酸化和通过IL-4受体快速诱导的转录因子酶-1的诱导。 骨髓衍生的巨噬细胞（BMDM）群体和单核细胞对IL-4非常敏感，但需要100至1000倍的IL-13才能达到相当的应答。 巧合的是，来自γ共同缺陷小鼠的BMDM对IL-13反应良好，但对IL-4反应较差，抗γ共同抗体基本上消除了单核细胞对IL-4的反应。 腹膜巨噬细胞和成纤维细胞对IL-4和IL-13均反应良好，并且γ共同缺失对IL-4或IL-13反应的影响非常小。 使用信息的受体亚基的数量和平衡常数为每个相互作用，一个模型已经推导出解释这些结果。 从分析中可以得出结论，IL-4作为分化诱导剂起着核心作用，而IL-13是主要的效应分子。 LI科学家还对嗜碱性粒细胞产生IL-4有了新的见解。 他们已经表明，这些细胞在蠕虫感染中大量募集到组织、脾脏和血液中，并且这种募集是T细胞依赖性的。 IL-3似乎在嗜碱性粒细胞募集中起主要作用。 实验室的科学家们已经研制出一系列指示鼠。 特别有价值的是反映IL-4和IL-13表达的那些。 这些指示小鼠是通过引入细菌人工染色体制成的，其中AM-Cyan基因取代了IL-4，不稳定的DS-Red取代了IL-13。这些小鼠已被证明是血吸虫感染中细胞因子产生的优秀报告者，其在其他感染中的价值正在研究中。

Summary Interleukin-4 is a prototypic type I cytokine that is the central regulator of allergic inflammatory responses. It controls the polarization of naive CD4 T cells to the TH2 phenotype and Ig class switching to IgE. The Cytokine Biology Unit has characterized the signaling mechanisms utilized by the IL-4 receptor. It has shown that activation of the latent transcription factor, Stat 6, controls both TH2 polarization and IgE class switching. Scientists in the Unit have established that both GATA3 and Stat5 are essential for acquisition of IL-4 producing capacity. They have recently carried out genome wide analyses of histone modification and transcription factor binding in each of the various Th lineages to gain insight into the processes underlying Th differentiation. They have made good progress in the study of the sites in the genome to which the master regulatory transcription factor GATA3 binds. This information coupled with knowledge of the binding sites for STAT5 promises to give important insights into the genetic regulation of Th2 differentiation. Comprable studies on the other Th lineages should provide similar information for the differentiation of those cells. Unit scientists have now been shown that T cell receptor-mediated activation of the erk signaling pathway blocks Th2 differentiation by preventing transcription of GATA3 and desensitizing the IL-2 receptor. Strong TCR-mediated signals stimulate erk phosphorylation, thereby preventing TH2 differentiation and accounting for poor Th2 differentiation at high antigen concentration. Low concentrations of antigen, which activate erk only weakly, are permissive for early IL-4 production and TH2 differentiation. Unit scientists have also shown that Notch signaling participates in Th2 primiing but that it doers so not by regulating GATA3, which others had proposed, but rather by regulating IL-2 production. Limited IL-2, by limiting STAT5, diminishes Th2 priming. The defect in Th2 priming in mice with defects in the Notch pathway can be rescued by the addiiton of IL-2. Gfi-1, in its role as a transcriptional repressor, is critical for robust growth to IL-2, since it appears to repress expression of genes such as SOCS1 and SOCS3 that inhibit IL-2 mediated growth. On the other hand, Gfi-1 diminishes growth in response to IL-7 since it mediates TCR- and cytokine-mediated down regulation of the IL-7R alpha chain. These studies, utilizing Gfi-1 conditional knockout mice developed in the Unit, establish that Gfi-1 plays a critical role in lymphocyte homeostasis and that precise regulation of Gfi-1 expression is central to a balanced population of CD4 and CD8 T cells. Further, Gfi-1 plays a central role in the phenotype of memory CD4 and CD8 cells induced by viral infection. More recently, it has been shown that Gfi-1 represses differentiation to the IL-17 and T%reg fates. Indeed, Gfi-1 appears to function as a repressor of fates alternate to Th2. Recently, Unit scientists have begun the analysis of the role of IL-1 family members in the regulation of T cell function. They have shown that IL-1 is a potent enhancer, acting directly on responding CD4 T cells, of cellular expansion in response to antigen. Addition of IL-1 to an immunization protocol can enhance T cell expansion by as much as 10-fold and strikingly enhance priming to Th17 ce;lls and to a lesser extent to Th2 cells. Uni scientists have also shown that differentiated Th effector cells can be stimulated to secrete key cytokines by stimulation with an IL-1 family member and by STAT activation. For Th1 cells, the IL-1 family member required is IL-18 and the STAT is STAT4; for Th2, IL-33 and STAT5 and for Th17, IL-1 and STAT3. In addition, an in depth effort to understand the distinctive signaling mechanisms used for IL-4 and IL-13 responses, with emphasis on the differential roles of the type I and type II IL-4 receptors and how different cell types show very different relative sensitivity to these congeners. For this purpose, responses of various macrophage populations from wild-type and gamma common-deficient mice to IL-4 and IL-13 have been analyzed in detail. Both the phosphorylation of STAT6, as measured by glow cytometric analysis, and the induction of arginase-1, a gene that is rapidly induced through the IL-4 receptor, has been evaluated. Bone marrow derived macrophage (BMDM) populations and monocytes are exquisitely sensitive to IL-4 but require 100 to 1000 fold more IL-13 to achieve a comparable response. Paradoxically, BMDM from gamma common-deficient mice respond well to IL-13 but poorly to IL-4 and anti- gamma common antibody essentially abolishes responses of monocytes to IL-4. Peritoneal macrophages and fibroblasts respond well to both IL-4 and IL-13 and gamma common deletion has very little effect on either IL-4 or IL-13 responses. Using information regarding the numbers of receptor subunits and equilibrium constants for each interaction, a model has been derived to explain these results. From the analysis, it has been concluded that IL-4 plays a central role as an inducer of differentiation while IL-13 is a major effector molecule. LI scientists have also developed new insights into the production of IL-4 by basophils. They have shown that these cells are massively recruited into the tissues, spleen and blood in helminth infection and that this recruitment is T cell dependent. IL-3 appears to play a major role in basophil recruitment. Laboratory scientists have developed a series of indicator mice. Particularly valuable are those that reflect the expression of IL-4 and IL-13. These indicator mice were made through the introduction of a bacterial artificial chromosome in which the AM-Cyan gene replaced IL-4 and destabilized DS-Red has replaced IL-13. These mice have proved to be excellent reporters of cytokine production in Schistomiasis infection and thier value in other infections is being studied.