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Originally published In Press as doi:10.1074/jbc.M110729200 on January 30, 2002

J. Biol. Chem., Vol. 277, Issue 15, 12689-12696, April 12, 2002
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Extracellular mRNA Induces Dendritic Cell Activation by Stimulating Tumor Necrosis Factor-alpha Secretion and Signaling through a Nucleotide Receptor*

Houping NiDagger , John CapodiciDagger , Georgetta CannonDagger , Didier Communi§, Jean-Marie Boeynaems§, Katalin Karikó, and Drew WeissmanDagger ||

From the Divisions of Dagger  Infectious Diseases and  Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the § Institute of Interdisciplinary Research and Department of Medical Chemistry, School of Medicine, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium

We previously demonstrated that dendritic cell (DC) pulsing with antigen-encoded mRNA resulted in the loading of both major histocompatibility complex class I and II antigen presentation pathways and the delivery of an activation signal. Coculture of mRNA-pulsed DC with T cells led to the induction of a potent primary immune response. DC, in addition to recognizing foreign antigens through pattern recognition receptors, also must respond to altered self, transformed, or intracellularly infected cells. This occurs through cell surface receptors that recognize products of inflammation and cell death. In this report, we characterize two signaling pathways utilized by extracellular mRNA to activate DC. In addition, a novel ligand, poly(A), is identified that mediates signaling through a receptor that can be inhibited by pertussis toxin and suramin and can be desensitized by ATP and ADP, suggesting a P2Y type nucleotide receptor. The role of this signaling activity in vaccine design and the potential effect of mRNA released by damaged cells in the induction of immune responsiveness is discussed.


* This work was supported by NHLBI, National Institutes of Health (NIH) Grant R01-HL-62060-1 and by NIAID, NIH Grant R21-AI-45318-01A1.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Division of Infectious Diseases, University of Pennsylvania, 522B Johnson Pavilion, Philadelphia, PA 19104. Tel.: 215-614-0291; Fax: 215-349-5111; E-mail: dreww@mail.med.upenn.edu.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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