p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes.
p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes.
复制标题
DOI：
10.4049/jimmunol.161.7.3225
复制
发表时间：
1998-10
影响因子：
4.4
通讯作者：
A. Craxton;G. Shu;J. Graves;J. Saklatvala;E. Krebs;E. Clark
中科院分区：
文献类型：
--
作者：
A. Craxton;G. Shu;J. Graves;J. Saklatvala;E. Krebs;E. Clark
我们研究了p38 MAPK通路在多种B细胞系和人扁桃体B细胞中对CD 40参与的响应，以确定p38 MAPK在增殖、NF-κ B活化和基因表达中的作用。交联CD 40快速刺激p38 MAPK及其下游效应物MAPKAPK-2。在完全阻止MAPKAPK-2激活的条件下，使用特异性细胞渗透性抑制剂SB 203580抑制体内p38 MAPK活性，强烈干扰CD 40诱导的扁桃体B细胞增殖，同时增强B细胞受体（BCR）驱动的增殖反应。SB 203580还显著降低了由含有四个NF-κ B元件的最小启动子驱动的报告基因的表达，表明在CD 40诱导的NF-κ B活化中需要p38 MAPK途径。然而，CD 40介导的NF-κ B结合不受SB 203580的影响，表明NF-κ B可能不是CD 40诱导的p38 MAPK通路的直接靶点。此外，SB 203580选择性地降低CD 40诱导的CD 54/ICAM-1表达，而CD 40和CD 95/Fas的CD 40依赖性表达以及四个新定义的CD 40响应基因cIAP 2、TRAF 1、TRAF 4/CART和DR 3不受影响。我们的观察结果表明，p38 MAPK途径是CD 40诱导的增殖所必需的，CD 40通过p38 MAPK依赖性和非依赖性途径诱导基因表达。
We have investigated the activation of the p38 MAPK pathway in response to CD40 engagement in multiple B cell lines and in human tonsillar B cells to define the role of p38 MAPK in proliferation, NF-kappaB activation and gene expression. Cross-linking CD40 rapidly stimulates both p38 MAPK and its downstream effector, MAPKAPK-2. Inhibition of p38 MAPK activity in vivo with the specific cell-permeable inhibitor, SB203580, under conditions that completely prevented MAPKAPK-2 activation, strongly perturbed CD40-induced tonsillar B cell proliferation while potentiating the B cell receptor (BCR)-driven proliferative response. SB203580 also significantly reduced expression of a reporter gene driven by a minimal promoter containing four NF-kappaB elements, indicating a requirement for the p38 MAPK pathway in CD40-induced NF-kappaB activation. However, CD40-mediated NF-kappaB binding was not affected by SB203580, suggesting that NF-kappaB may not be a direct target for the CD40-induced p38 MAPK pathway. In addition, SB203580 selectively reduced CD40-induced CD54/ICAM-1 expression, whereas CD40-dependent expression of CD40 and CD95/Fas and four newly defined CD40-responsive genes cIAP2, TRAF1, TRAF4/CART and DR3 were unaffected. Our observations show that the p38 MAPK pathway is required for CD40-induced proliferation and that CD40 induces gene expression via both p38 MAPK-dependent and -independent pathways.