Interleukin 4

白细胞介素4

基本信息

批准号：
7732461
负责人：
William Paul
金额：
$ 149.35万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS 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/7732461
关键词：
Accounting Alleles Allergic Antibodies Antigens Basophils Binding Biology Blood Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chromatin Depth Differentiation Inducer Down-Regulation Effector Cell Employee Strikes Equilibrium Fibroblasts Gene Activation Gene Expression Genes Genetic Transcription Goals Growth Half-Life Hand Helminths Histone Acetylation Histones Homeostasis IL4 gene IgE Immunoglobulin Class Switching In Vitro Individual Infection Inflammation Inflammatory Response Interleukin 2 Receptor Interleukin 4 Receptor Interleukin-13 Interleukin-17 Interleukin-2 Interleukin-3 Interleukin-4 Interleukin-5 Interleukin-7 Intervention Ionomycin Knockout Mice Laboratory Scientists Lead Lymphocyte MAPK14 gene Measures Mediating Memory Messenger RNA Microarray Analysis Mitogen-Activated Protein Kinases Modeling Molecular Mus Notch Signaling Pathway Numbers Peritoneal Macrophages Phenotype Phosphorylation Play Population Production Proteins Purpose Recruitment Activity Regulation Relative (related person)Reporter Rest Role STAT6 gene Schistosoma mansoni Scientist Signal Pathway Signal Transduction Site Spleen Staging T-Cell Receptor T-Lymphocyte Techniques Th2 Cells Tissues Transcription Repressor/Corepressor Ursidae Family Virus Diseases alpha chain interleukin-7 receptor arginase cell growth cell type chromatin immunoprecipitation cytokine expression cloning genome-wide analysis in vivo insight macrophage monocyte new technology notch protein prevent receptor response transcription factor

项目摘要

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 and havve identified the sites in the IL-4 gene to which these transcription factors bind. It has now been shown that T cell receptor-mediated activation of the erk signaling pathway prevents transcription of GATA3 and desensitizes the IL-2 receptor. Since GATA3 and IL-2/ STat5 are essential for early transcription of IL-4, which in turn controls TH2 differentiation, erk activation prevents Th2 commitment. High concentrations of antigen strongly 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. Recently, it has been proposed that activation of the Notch signaling pathway is essential for TCR-mediated GATA3 activation. However, using mice that are conditionally deleted in genes key to Notch signaling (presinilin 1 and 2 or CSL), no abnormalities in TCR-induced GATA3 could be shown. Rather, IL-2 production was defective and Th2 polarization could be resuced by the addition of IL-2. Utilizing conditional GATA3 knockout mice prepared by scientists in the Unit, it has been shown that GATA3 is essential for priming for IL-4-production both in vitro and in vivo but that cells that have already differentiated into Th2 cells can sustain their IL-4 producing capacity even when GATA3 is eliminated. By contrast, both IL-5 and IL-13 production are strictly dependent on GATA3. It has been further demonstrated that GATA3 is a potent growth regulator of TH2 cells and that GATA3 and Gfi-1 act together to induce this striking stimulation of TH2 cell growth. Indeed, Gfi-1 conditional knockout mice show a major diminution in Th2 responses in S. mansoni infections due to diminished growth of these cells. 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. p38 has now been shown to play a major role in IL-4 expression. Its function is mediated, at least in part, through its regulation of IL-4 mRNA half-life. Th2 cells in which p38 has been activated display long IL-4 mRNA half-lives but if p38 fails to be activated or if its activity is blocked, most IL-4 mRNA has been degraded within 30 minutes. Unit scientists have shown that recently activated Th2 cells robustly activate p38 in response to stimulation but that resting memory cells show poor activation, suggesting that effector cells have a striking advantage in the capacity to produce IL-4, at least in part due to their capacity to sustain IL-4 mRNA. Ionomycin alone can initiate IL-4 production by memory Th2 cells. This appears to result from the phosphorylation of MAP kinases upstream of p38 including ASK and TAC, resulting in p38 activation, as well as the activation of the NFAT signaling pathway. A further in depth analysis of the distinctiveness of the various differentiated populations of CD4 T cells including TH2, TH1 and TH17 cells has been undertaken through a genome-wide analysis of distinctive sites for histone acetylation in each of these differentiated populations. Using new technology for high throughput sequencing combined with chromatin immunoprecipitation, an analysis has been done of those sites that show high levels of association with acetylated histone and they have been compared to genes that show evidence of activation using microarray analysis. The correlation has been very good. Additional use of this extremely powerful approach to understand global gene activation during differentiation will be undertaken. Laboratory scientists have also demonstrated that the transcription of the two alleles at the IL-4 locus is governed stochastically and that the likelihood of transcription is associated with the degree of chromatin accessibility of the two alleles. Furthermore, although there are shared requirements for the transcription of IL-4 and IL-13, in individual cells and individual clones, the expression of these cytokines is independently determined. To study this in greater detail, scientists in the Cytokine Biology Unit are using the techniques of recombineering to develop mice that bear fluorescent protein reporters for expression of IL-4 and IL-13. 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.

概括白介素-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剂。它控制着幼稚的CD4 T细胞对Th2表型的极化，并切换到IgE。细胞因子生物学单元已经表征了IL-4受体使用的信号传导机制。它表明，潜在转录因子STAT 6的激活控制TH2极化和IgE类切换。该单元中的科学家已经确定，GATA3和STAT5对于获得IL-4产生能力至关重要，而Havve则确定了这些转录因子与之结合的IL-4基因中的位点。现在已经显示，T细胞受体介导的ERK信号通路的激活阻止了GATA3的转录并使IL-2受体脱敏。由于GATA3和IL-2/ STAT5对于IL-4的早期转录至关重要，IL-4又控制TH2分化，因此ERK激活阻止了TH2承诺。高浓度的抗原强烈刺激ERK磷酸化，从而防止Th2分化并考虑到高抗原浓度下Th2分化差。低浓度的抗原仅弱激活ERK，可以允许早期IL-4产生和Th2分化。最近，已经提出，Notch信号通路的激活对于TCR介导的GATA3激活至关重要。但是，使用在Notch信号转导的基因键（Persinilin 1和2或CSL）中有条件删除的小鼠，可以显示TCR诱导的GATA3异常。相反，IL-2的产生是有缺陷的，可以通过添加IL-2恢复Th2极化。利用该单元中科学家制备的条件GATA3敲除小鼠，已经表明，GATA3对于在体外和体内进行IL-4产生的启动至关重要，但是即使消除GATA3被消除了，已经区分了TH2细胞的细胞也可以维持其IL-4生产能力。相比之下，IL-5和IL-13的产生都严格取决于GATA3。已经进一步证明了GATA3是Th2细胞的有效生长调节剂，GATA3和GFI-1共同起作用，诱导了对Th2细胞生长的惊人刺激。实际上，由于这些细胞的生长减少，GFI-1条件敲除小鼠在曼氏链球菌感染中的Th2反应显着减少。 GFI-1在其作为转录阻遏物的作用中对于对IL-2的稳健生长至关重要，因为它似乎抑制了抑制IL-2抑制IL-2介导的生长的基因的表达。另一方面，GFI-1会减少对IL-7的响应，因为它介导了IL-7Rα链的TCR和细胞因子介导的下调调节。这些研究利用该单元中开发的GFI-1条件敲除小鼠，确定GFI-1在淋巴细胞稳态中起着至关重要的作用，而GFI-1表达的精确调节对于CD4和CD8 T细胞的平衡群体至关重要。此外，GFI-1在病毒感染诱导的记忆CD4和CD8细胞的表型中起着核心作用。最近，已经表明，GFI-1抑制了与IL-17和T％Reg命运的分化。实际上，GFI-1似乎是命运的阻遏物，替代TH2。现在已显示p38在IL-4表达中起主要作用。它的功能至少部分是通过调节IL-4 mRNA半衰期介导的。激活p38的Th2细胞显示长IL-4 mRNA半衰期，但如果p38无法激活或其活性被阻断，则大多数IL-4 mRNA在30分钟内已降解。单位科学家表明，最近激活的Th2细胞可响应刺激而牢固地激活p38，但静止记忆细胞的激活不佳，这表明效应细胞在产生IL-4的能力上具有惊人的优势，至少部分是由于它们维持IL-4 mRNA的能力。仅离子霉素就可以通过记忆Th2细胞引发IL-4产生。这似乎是由P38上游的MAP激酶的磷酸化引起的，包括Ask和TAC，导致p38激活以及NFAT信号通路的激活。通过对所有这些分化群体中的组蛋白乙酰化的独特位点的分析，对CD4 T细胞（包括Th2，Th1和Th17细胞）的各种分化群体的独特性进行了进一步的深入分析。使用新技术进行高通量测序与染色质免疫沉淀结合，已经对那些显示出与乙酰化组蛋白相关的位点进行了分析，并且已将其与使用微阵列分析显示激活的证据的基因进行了比较。相关性非常好。将继续使用这种极有力的方法来了解分化过程中的全球基因激活。实验室科学家还表明，IL-4基因座的两个等位基因的转录受到随机控制，并且转录的可能性与两个等位基因的染色质可及性程度有关。此外，尽管在单个细胞和单个克隆中，对IL-4和IL-13的转录有共同的要求，但这些细胞因子的表达是独立确定的。为了更详细地研究这一点，细胞因子生物学单元的科学家正在使用重新组合的技术来开发带有荧光蛋白报道的小鼠，以表达IL-4和IL-13。此外，深入了解用于IL-4和IL-13响应的独特信号传导机制，重点是I型和II型IL-4受体的差异作用，以及不同的细胞类型如何表现出与这些同类物的相对敏感性非常不同。为此，已经详细分析了野生型和伽马共同缺陷小鼠对IL-4和IL-13的各种巨噬细胞种群的反应。通过GLOW细胞术分析测量的STAT6的磷酸化以及精氨酸酶-1的诱导是通过IL-4受体迅速诱导的基因。骨髓衍生的巨噬细胞（BMDM）种群和单核细胞对IL-4非常敏感，但需要100至1000倍的IL-13才能达到可比的响应。矛盾的是，来自伽马共同缺陷小鼠的BMDM对IL-13的反应良好，但对IL-4的反应较差，而抗伽马常见抗体基本上废除了单核细胞对IL-4的反应。腹膜巨噬细胞和成纤维细胞对IL-4和IL-13的反应良好，而伽马常见缺失对IL-4或IL-13响应的影响很小。使用有关每种相互作用的受体亚基和平衡常数的信息，已得出一个模型来解释这些结果。从分析中可以得出结论，IL-4在分化的诱导剂中起着核心作用，而IL-13是主要的效应分子。李科学家还开发了新的见解，对嗜碱性粒细胞对IL-4的生产产生了新的见解。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细胞依赖的。 IL-3似乎在嗜碱性粒细胞招募中起着重要作用。

项目成果

期刊论文数量（48）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile.

DOI：
10.4049/jimmunol.163.1.337
发表时间：
1999-07
期刊：
Journal of immunology
影响因子：
4.4
作者：
Dragana Jankovic;M. Kullberg;N. Noben-Trauth;P. Caspar;J. Ward;A. Cheever;W. Paul;A. Sher
通讯作者：
Dragana Jankovic;M. Kullberg;N. Noben-Trauth;P. Caspar;J. Ward;A. Cheever;W. Paul;A. Sher

BCL-6-deficient mice reveal an IL-4-independent, STAT6-dependent pathway that controls susceptibility to infection by Leishmania major.

BCL-6 缺陷小鼠揭示了一条不依赖 IL-4、依赖 STAT6 的途径，可控制对重大利什曼原虫感染的易感性。

DOI：
发表时间：
1999
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Dent,AL;Doherty,TM;Paul,WE;Sher,A;Staudt,LM
通讯作者：
Staudt,LM

A critical control element for interleukin-4 memory expression in T helper lymphocytes.

T 辅助淋巴细胞中白细胞介素 4 记忆表达的关键控制元件。

DOI：
10.1074/jbc.m502038200
发表时间：
2005
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Tykocinski,Lars-Oliver;Hajkova,Petra;Chang,Hyun-Dong;Stamm,Torsten;Sozeri,Osman;Lohning,Max;Hu-Li,Jane;Niesner,Uwe;Kreher,Stephan;Friedrich,Beate;Pannetier,Christophe;Grutz,Gerald;Walter,Jorn;Paul,WilliamE;Radbruch,Andreas
通讯作者：
Radbruch,Andreas

Fibrosin, a novel fibrogenic cytokine, modulates expression of myofibroblasts.

纤维蛋白是一种新型的纤维形成细胞因子，调节肌成纤维细胞的表达。