P38 MAPK IS REQUIRED FOR CD40-INDUCED GENE-EXPRESSION AND PROLIFERATION IN B-LYMPHOCYTES

We have investigated the activation of the p38 MAPK pathway in respons e to CD40 engagement in multiple B cell lines and in human tonsillar B cells to define the role of p38 MAPK in proliferation, NF-kappa B act ivation and gene expression. Cross-linking CD40 rapidly stimulates bot h p38 MAPK and its downstream effector, MAPKAPK-2. Inhibition of p38 M APK activity in vivo with the specific cell-permeable inhibitor, SB203 580, under conditions that completely prevented MAPKAPK-2 activation, strongly perturbed CD40-induced tonsillar B cell proliferation while p otentiating the B cell receptor (BCR)-driven proliferative response. S B203580 also significantly reduced expression of a reporter gene drive n by a minimal promoter containing four NF-kappa B elements, indicatin g a requirement for the p38 MAPK pathway in CD40-induced NF-kappa B ac tivation. However, CD40-mediated NF-kappa B binding was not affected b y SB203580, suggesting that NF-kappa B may not be a direct target for the CD40-induced p38 MAPK pathway. In addition, SB203580 selectively r educed CD40-induced CD54/ICAM-1 expression, whereas CD40-dependent exp ression of CD40 and CD95/Fas and four newly defined CD40-responsive ge nes cIAP2, TRAF1, TRAF4/CART and DR3 were unaffected. Our observations show that the p38 MAPK pathway is required for CD40-induced prolifera tion and that CD40 induces gene expression via both p38 MAPK-dependent and -independent pathways.