IgE switching requires the prior induction of Ce germline transcripts which is mediated by the concerted binding of STAT-6 and NFkB to the Ce promoter. These transcription factors are regulated by IL-4 and CD40, respectively. However the latter can effect other signaling pathways and the present study explores the role of p38 MAPK in induction of Ce germline transcripts. CD40 and IL-4, both alone and in synergy, were initially shown to activate the Ce promoter in a B cell lymphoma cell line. Under the same conditions CD40 caused activation of p38 MAPK, whereas IL-4 was ineffective. The p38 MAPK inhibitor, SB203580, and a dominant negative form of p38 MAPK decreased the CD40 activation of the Ce promoter by reducing the ability of CD40 to increase the transactivation potential of NFkB. This study suggests that p38 MAPK is crucially important in mediating CD40 activation of NFkB which acts to induce Ce germline transcripts, ultimately facilitating IgE switching.