Maltzman J S, Carmen J A, Monroe J G
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
J Exp Med. 1996 Apr 1;183(4):1747-59. doi: 10.1084/jem.183.4.1747.
Intercellular adhesion molecule (ICAM) 1/CD54 plays an important role in T cell dependent B cell activation and for function of B lymphocytes as antigen-presenting cells. ICAM-1 expression is upregulated as a consequence of B lymphocyte antigen receptor (BCR) signaling, thereby serving to render antigen-stimulated B cells more receptive to T cell-mediated costimulatory signals. We have investigated BCR-induced expression of the Icam-1 gene in primary B cells and B cell lines and have found it to be dependent on BCR-induced expression of the transcription factor EGR1. Icam-1 transcription, induced by BCR cross-linking or bypassing the BCR with phorbol ester, is absent in a B cell line in which the EGR1-encoding gene (egr-1) is methylated and not expressed. A potential EGR1-binding site was located at -701 bp upstream of the murine Icam-1 gene transcription start site and shown by electrophoretic mobility shift assay to bind to murine EGR1. Mutation of this site in the context of 1.1 kb of the Icam-1 promoter significantly abrogated transcriptional induction by phorbol ester and anti-mu stimulation in primary B cells. A direct effect of EGR1 on the Icam-1 promoter is suggested by the ability of EGR1 expressed from an SV40-driven expression vector transactivate the wild-type Icam-1 promoter, whereas mutation of the EGR1 mutation of the EGR1 binding motif at -701 bp markedly compromises this induction. These data identify EGR1 as a signaling intermediate in BCR-stimulated B cell functional responses, specifically linking BCR signal transduction to induction of the Icam-1 gene. Furthermore, similar findings for BCR-induced CD44 gene induction (Maltzman, J.S., J.A. Carman, and J.G. Monroe. 1996. Role of EGR1 in regulation of stimulus-dependent CD44 transcription in B lymphocytes. Mol. Cell. Biol. In press) suggest that EGR1 may be an important signaling molecule for regulating levels of migration and adhesion molecules during humoral immune responses.
细胞间黏附分子（ICAM）1/CD54在T细胞依赖性B细胞活化以及B淋巴细胞作为抗原呈递细胞的功能中发挥重要作用。作为B淋巴细胞抗原受体（BCR）信号传导的结果，ICAM-1表达上调，从而使抗原刺激的B细胞更易接受T细胞介导的共刺激信号。我们研究了BCR诱导的Icam-1基因在原代B细胞和B细胞系中的表达，发现其依赖于BCR诱导的转录因子EGR1的表达。在编码EGR1的基因（egr-1）甲基化且不表达的B细胞系中，BCR交联或用佛波酯绕过BCR诱导的Icam-1转录缺失。一个潜在的EGR1结合位点位于小鼠Icam-1基因转录起始位点上游-701 bp处，电泳迁移率变动分析表明其可与小鼠EGR1结合。在1.1 kb的Icam-1启动子背景下该位点的突变显著消除了佛波酯和抗μ刺激在原代B细胞中诱导的转录。由SV40驱动的表达载体表达的EGR1能够反式激活野生型Icam-1启动子，这提示EGR1对Icam-1启动子有直接作用，而-701 bp处EGR1结合基序的突变显著损害了这种诱导作用。这些数据确定EGR1是BCR刺激的B细胞功能反应中的信号中间体，具体地将BCR信号转导与Icam-1基因的诱导联系起来。此外，关于BCR诱导的CD44基因诱导的类似发现（Maltzman, J.S., J.A. Carman, and J.G. Monroe. 1996. Role of EGR1 in regulation of stimulus-dependent CD44 transcription in B lymphocytes. Mol. Cell. Biol. In press）表明，EGR1可能是体液免疫反应期间调节迁移和黏附分子水平的重要信号分子。
