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*
Department of Microbiology, University of Washington, Seattle, WA 98195; and
Robert-Roessle-Klinik, Charite, Humboldt University of Berlin, Berlin, Germany
We investigated whether human monocyte-derived dendritic cells
(DCs) differed from tonsillar B cells in the set of cell fate genes
they express constitutively and in the way these genes are affected
after CD40 ligation. In particular, Bcl-2, TNF receptor-associated
factor-2 (TRAF2), and TRAF4 were clearly inducible via CD40 in B cells
but not in DCs. DCs, unlike B cells, were induced to increase
expression of IL-1ß, IL-1Ra, IL-8, IL-12 p40, RANTES, macrophage
inflammatory protein-1
, and monocyte chemoattractant protein-1 after
CD40 ligation. We next tested whether CD40-induced signaling pathways
were different in DCs vs B cells. In DCs, as in B cells, CD40 ligation
activated p38 mitogen-activated protein kinase (MAPK), its downstream
target, MAPKAPK-2, and the c-Jun N-terminal kinase. The p38
MAPK-specific inhibitor, SB203580, blocked CD40-induced MAPKAPK-2
activation, but did not affect activation of c-Jun N-terminal kinase.
Furthermore, unlike in B cells, extracellular signal-regulated kinase-1
and -2 were activated after CD40 ligation in DCs. SB203580 strongly
blocked CD40-induced IL-12 p40 production in DCs at both mRNA and
protein levels, while having minimal effect on CD40-induced expression
of the chemokine RANTES. In contrast, no detectable IL-12 p40 protein
was secreted in CD40-stimulated B cells. Furthermore, CD40-induced mRNA
expression of cellular inhibitor of apoptosis protein-2 was 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 cellular inhibitor of apoptosis protein-2) is different from that
in B cells (IL-10 and IL-1ß).
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