Differential role for p38 mitogen-activated protein kinase in regulating CD40-induced gene expression in dendritic cells and B cells

We investigated whether human monocyte-derived dendritic cells (DCs) differ ed from tonsillar B cells in the set of cell fate genes they express consti tutively and in the way these genes are affected after CD40 ligation. In pa rticular, Bcl-2, TNF receptor-associated factor-2 (TRAF2), and TRAM were cl early inducible via CD40 in B cells but not in DCs, DCs, unlike a cells, we re induced to increase expression of IL-1 beta, IL-1Ra, IL-8, IL-12 p40, RA NTES, macrophage inflammatory protein-1 alpha, and monocyte chemoattractant protein-1 after CD40 ligation. We next tested whether CD40-induced signali ng pathways were different in DCs vs B cells. In DCs, as in B cells, CD40 l igation activated p38 mitogen-activated protein kinase (MAPK), its downstre am target, MAPKAPK-2, and the c-Jun N-terminal kinase. The p38 MAPK-specifi c inhibitor, SB203580, blocked CD40-induced MAPKAPK3 activation, but did no t affect activation of c-Jun N-terminal kinase. Furthermore, unlike in B ce lls, extracellular signal-regulated kinase-1 and -2 were activated after CD 40 ligation in DCs, SB203580 strongly blocked CD40-induced IL-12 p40 produc tion in DCs at both mRNA and protein levels, while having minimal effect on CD40-induced expression of the chemokine RANTES, In contrast, no detectabl e IL-12 p40 protein was secreted in CD40-stimulated B cells. Furthermore, C D40-induced mRNA expression of cellular inhibitor of apoptosis protein-2 wa s also dependent on the p38 MAPK pathway in DCs and differed compared with that in B cells. In conclusion, CD40 induces distinct programs in DCs and B cells, and the set of p38 MAPK-dependent genes in DCs (IL-12 p40 and cellu lar inhibitor of apoptosis protein-2) is different from that in B cells (IL -10 and IL-1 beta).