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) 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-1beta, IL-1Ra, IL-8, IL-12 p40, RANTES, macrophage inflammatory protein-1alpha, 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-1beta).
Aicher
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Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Shu
G L
GL
Magaletti
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Mulvania
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T
Pezzutto
A
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Craxton
A
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Clark
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EA
D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007152:Immunologic Capping; D051034:Inhibitor of Apoptosis Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1; D048008:TNF Receptor-Associated Factor 3; D053449:TNF Receptor-Associated Factor 4; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D018925:Chemokines; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D047990:TNF Receptor-Associated Factor 1; D048008:TNF Receptor-Associated Factor 3; D053449:TNF Receptor-Associated Factor 4; C506367:TRAF4 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases