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REGULATORY MECHANISMS OF IL-5 DEPENDENT IMMUNE REGULATION

IL-5依赖性免疫调节的调节机制

基本信息

批准号：
13307012
负责人：
TAKATSU Kiyoshi
金额：
$ 35.36万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Interleukin 5 (IL-5) induces proliferation and differentiation of B cells by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, α and β(βc). In this project, we attempted to elucidate the role of IL-5 in B-cell proliferation and differentiation. We found that the IL-5/IL-5R system plays an important role in maintaining the number and the cell size as well as the functions of mature B-1 cells. The administration of anti-IL-5 mAb into wild-type (WT) mice, T -cell-depleted mice or mast cell-depleted mice resulted in reduction in the total number and cell size of B-1 cells to a similar extent to IL-5Rα-deficient (IL-5Rα^<-/->) mice. Cell transfer experiments have demonstrated that B-1 cell survival in WT mice and homeostatic proliferation in RAG-2^<-/-> mice are impaired in the absence of the IL-5Rα. IL-5 stimulation of WT B-1 cells, but not IL-5Rα ^<-/-> B-1 cells, enhances CD40 expression and augments IgM and IgG production following stimulation with … More anti-CD40 mAb. Enhanced IgA production in feces induced by the oral administration of LPS was not observed in IL-5Rα^<-/-> mice. Our results illuminate the role of IL-5 in the homeostatic proliferation and survival of mature B-1 cells and in IgA production in the mucosal tissues.IL-5 stimulation of CD38-activated murine splenic B cells induces μ-γ1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent m-g1 CSR. We examined the activation of Stat by IL-5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells. The role of Stat5a and Stat5b in IL-5-induced μ-γ1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a^<-/-> / and Stat5b^<-/-> mice. Expression levels of CD38-induced germline γ1 transcripts and of AID in Stat5a^<-/-> /-and Stat5b^<-/->/ B cells upon IL-5 stimulation were comparable to those of WT B cells. The impaired μ-γ1 CSR by Stat5b^<-/-> B cells, but not by Stat5a^<-/-> / B cells, was rescued in part by IL-4. Analysis of cell division cycle number of WT B cells revealed that μ-γ1 CSR was observed after five to six cell divisions. Stat5a^<-/-> / and Stat5b^<-/->/ B cells showed similar cell division cycles, but they did not undergo μ-γ1 CSR. Our data supports the notion that both Stat5a and Stat5b are essential for IL-S-dependent μ-γ1 CSR and Ig secretion, however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function. Less

白细胞介素5（IL-5）通过与其受体（IL-5 R）相互作用诱导B细胞增殖和分化。在这个项目中，我们试图阐明IL-5在B细胞增殖和分化中的作用。我们发现IL-5/IL-5 R系统在维持成熟B-1细胞的数量、大小和功能方面起着重要作用。将抗IL-5 mAb给予野生型（WT）小鼠、T细胞耗竭小鼠或肥大细胞耗竭小鼠导致B-1细胞总数和细胞大小减少，其程度与IL-5 R α缺陷（IL-5 R α^<-/->）小鼠相似。细胞转移实验已经证明，在不存在IL-5 R α的情况下，WT小鼠中的B-1细胞存活和RAG-2^<-/->小鼠中的稳态增殖受损。IL-5刺激WT B-1细胞，而不是IL-5 R α ^<-/-> B-1细胞，在用IL-5刺激后增强CD 40表达并增加IgM和IgG产生。 ...更多信息 anti-CD40 mAb.在IL-5 R α^<-/->小鼠中未观察到经口给予LPS诱导的粪便中伊加产生的增强。我们的结果阐明了IL-5在成熟B-1细胞的稳态增殖和存活以及粘膜组织中伊加产生中的作用。IL-5刺激CD 38激活的小鼠脾B细胞在DNA水平诱导μ-γ1类转换重组（CSR），导致高水平的IgG 1产生。在系统中进一步添加IL-4增强IL-5依赖性m-g1 CSR。我们检测了IL-5和CD 38激活的小鼠脾B细胞中激活诱导的胞苷脱氨酶（AID）对Stat的激活。记录了Stat 5a和Stat 5 B在IL-5诱导的μ-γ1 CSR以及IgG 1和IgM产生中的作用，因为IL-5不作用于来自Stat 5a ^<-/->和Stat 5 B ^<-/->小鼠的CD 38刺激的脾B细胞。IL-5刺激后，Stat 5 a ^<-/-> /-和Stat 5 B ^<-/->/ B细胞中CD 38诱导的生殖系γ1转录物和AID的表达水平与WT B细胞的表达水平相当。由Stat 5 B ^<-/-> B细胞而不是由Stat 5 a ^<-/-> / B细胞引起的受损的μ-γ1 CSR被IL-4部分地挽救。对WT B细胞分裂周期数的分析表明，在5 - 6次细胞分裂后观察到μ-γ1 CSR。Stat 5a ^<-/-> /和Stat 5 B ^<-/->/ B细胞显示相似的细胞分裂周期，但它们不经历μ-γ1 CSR。我们的数据支持Stat 5a和Stat 5 b对于IL-5依赖性μ-γ1 CSR和IG分泌都是必需的这一观点，然而，它们的主要靶标可能不是AID。Stat 5a和Stat 5 b不是冗余的，而是至少在功能上部分不同。少