The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2175/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 11, December 7, 1998 2175-2180

Brief Definitive Reports

Dendritic Cell Survival and Maturation Are Regulated by Different Signaling Pathways

Maria Rescigno*, Manuela Martino*, Claire L. Sutherland{ddagger}, Michael R. Gold{ddagger}, and Paola Ricciardi-Castagnoli*

From the * Consiglio Nazionale delle Ricerche Center of Molecular and Cellular Pharmacology and the Department of Biotechnology and Biological Sciences, Second University of Milano, 20126 Milano, Italy; and the {ddagger} Department of Microbiology and Immunology, University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada

Although dendritic cell (DC) activation is a critical event for the induction of immune responses, the signaling pathways involved in this process have not been characterized. In this report, we show that DC activation induced by lipopolysaccharide (LPS) can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival). Using a DC culture system that allowed us to propagate immature growth factor–dependent DCs, we have investigated the signaling pathways activated by LPS. We found that LPS induced nuclear translocation of the nuclear factor (NF)-{kappa}B transcription factor. Inhibition of NF-{kappa}B activation blocked maturation of DCs in terms of upregulation of major histocompatibility complex and costimulatory molecules. In addition, we found that LPS activated the extracellular signal–regulated kinase (ERK), and that specific inhibition of MEK1, the kinase which activates ERK, abrogated the ability of LPS to prevent apoptosis but did not inhibit DC maturation or NF-{kappa}B nuclear translocation. These results indicate that ERK and NF-{kappa}B regulate different aspects of LPS-induced DC activation: ERK regulates DC survival whereas NF-{kappa}B is responsible for DC maturation.

Key Words: dendritic cells • maturation • survival • mitogen activated protein kinases • nuclear factor {kappa}B

Address correspondence to Paola Ricciardi-Castagnoli, CNR Center of Molecular and Cellular Pharmacology, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy. Phone: 39-2-7014-6283; Fax: 39-2-7014-6373; E-mail: paola{at}farma8.csfic.mi.cnr.it


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