Craxton A, Shu G, Graves J D, Saklatvala J, Krebs E G, Clark E A
Department of Microbiology, University of Washington, Seattle 98195, USA.
J Immunol. 1998 Oct 1;161(7):3225-36.
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.
我们研究了多条B细胞系及人扁桃体B细胞中p38丝裂原活化蛋白激酶（MAPK）通路对CD40激活的响应，以明确p38 MAPK在增殖、核因子κB（NF-κB）激活及基因表达中的作用。交联CD40可迅速刺激p38 MAPK及其下游效应分子MAPKAPK-2。在完全阻止MAPKAPK-2激活的条件下，用特异性细胞可渗透抑制剂SB203580在体内抑制p38 MAPK活性，强烈干扰了CD40诱导的扁桃体B细胞增殖，同时增强了B细胞受体（BCR）驱动的增殖反应。SB203580还显著降低了由含四个NF-κB元件的最小启动子驱动的报告基因的表达，表明CD40诱导的NF-κB激活需要p38 MAPK通路。然而，CD40介导的NF-κB结合不受SB203580影响，提示NF-κB可能不是CD40诱导的p38 MAPK通路的直接靶点。此外，SB203580选择性降低了CD40诱导的CD54/细胞间黏附分子-1（ICAM-1）表达，而CD40、CD95/Fas的CD40依赖性表达以及四个新定义的CD40反应性基因cIAP2、TRAF1、TRAF4/CART和DR3不受影响。我们的观察结果表明，p38 MAPK通路是CD40诱导增殖所必需的，且CD40通过p38 MAPK依赖性和非依赖性途径诱导基因表达。
