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

白介素5（IL-5）通过与其接收器（IL-5R）相互作用，诱导B细胞的增殖和分化，该接收器由两个不同的多肽链α和β（βC）组成。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-5R系统在维持数量和细胞大小以及成熟B-1细胞的功能方面起着重要作用。抗IL-5 MAB在野生型（WT）小鼠，T细胞缺乏的小鼠或肥大细胞耗尽的小鼠中的给药导致B-1细胞的总数和细胞大小的降低，其程度与IL-5R-5Rα-缺乏症的程度相似（IL-5Rα-缺乏症（IL-5Rα^<-/ - >）小鼠。细胞转移实验表明，在没有IL-5Rα的情况下，wt小鼠中的B-1细胞存活和rag-2^< - / - >小鼠的稳态增殖受到了损害。 WT B-1细胞的IL-5模拟，而不是IL-5Rα ^< - / - > B-1细胞，可增强CD40的表达，并增强使用…更多抗CD40 mAb刺激后的IgM和IgG产生。在IL-5Rα^< - / - >小鼠中未观察到由LPS口服诱导的粪便中的IgA产生增强。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中以及在粘膜组织中IgA产生中的作用。IL-5模拟CD38激活的鼠脾脏B细胞在DNA水平上诱导μ-γ1类别切换（CSR）诱导μ-γ1类别切换（CSR），从而导致IgG1的高水平IGG1生产。在系统中进一步添加IL-4可以增强IL-5依赖性M-G1 CSR。我们检查了CD38激活的鼠脾脏B细胞中IL-5和激活诱导的胞苷脱氨酶（AID）的STAT激活。记录了STAT5a和Stat5b在IL-5诱导的μ-γ1CSR以及IgG1和IgM产生中的作用，因为IL-5不对来自STAT5A^< - >/和Stat5B^<-/ - >小鼠的CD38刺激的脾脏B细胞作用。在IL-5模拟时，CD38诱导的种系γ1转录本和STAT5A^< - / - >/ - 和STAT5B^< - / - >/B细胞中的AID的表达水平与WT B细胞的表达水平相当。 STAT5B^< - / - > B细胞受损的μ-γ1CSR，但不是STAT5A^< - / - >/B细胞，部分由IL-4响应。 WT B细胞细胞分裂周期数的分析表明，在五到六个细胞分裂后观察到μ-γ1CSR。 STAT5A^< - / - >/和Stat5b^< - / - >/ B细胞显示出相似的细胞分裂周期，但它们没有经历μ-γ1CSR。我们的数据支持以下概念：STAT5A和STAT5B对于IL-S依赖性μ-γ1CSR和Ig分泌都是必不可少的，但是，它们的主要靶标可能不是辅助。 STAT5A和STAT5B不是多余的，而是其功能至少有部分独特。较少的