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Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function1
* Department of Nephrology and Hypertension,
Interdisciplinary Center of Clinical Research,
Institute for Microbiology, and
Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany; and
¶ Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
Dendritic cells (DC) play a key role in linking innate and adaptive immunity. In inflamed tissues, where DC become activated, oxygen tensions are usually low. Although hypoxia is increasingly recognized as an important determinant of cellular functions, the consequences of hypoxia and the role of one of the key players in hypoxic gene regulation, the transcription factor hypoxia inducible factor 1
(HIF-1), are largely unknown. Thus, we investigated the effects of hypoxia and HIF-1 on murine DC activation and function in the presence or absence of an exogenous inflammatory stimulus. Hypoxia alone did not activate murine DC, but hypoxia combined with LPS led to marked increases in expression of costimulatory molecules, proinflammatory cytokine synthesis, and induction of allogeneic lymphocyte proliferation compared with LPS alone. This DC activation was accompanied by accumulation of HIF-1 protein levels, induction of glycolytic HIF target genes, and enhanced glycolytic activity. Using RNA interference techniques, knockdown of HIF-1 significantly reduced glucose use in DC, inhibited maturation, and led to an impaired capability to stimulate allogeneic T cells. Alltogether, our data indicate that HIF-1 and hypoxia play a crucial role for DC activation in inflammatory states, which is highly dependent on glycolysis even in the presence of oxygen.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by an intramural grant (ELAN 06.08.04.1) to C.W. and J.J., and by grants from the Interdisciplinary Center for Clinical Research at the University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg to J.J., C.W., M.H., and A.S. Parts of this project were also supported by grants from the Deutsche Forschungsgemeinschaft to M.H., C.W., and K.-U.E. (SFB 423) and to A.S. (SFB 643). J.J. received a scholarship of the the Interdisciplinary Center for Clinical Research at the University Hospital Erlangen-Friedrich-Alexander University of Erlangen-Nuremberg.
2 Current address: Boehringer-Ingelheim Pharma, Biberach, Germany.
3 Address correspondence and reprint requests to Dr. Carsten Willam, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany. E-mail address: carsten.willam{at}med4.med.uni-erlangen.de or Dr. Michael Hensel, Institute for Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Wasserturmstrasse 3-5, D-91054 Erlangen, Germany. E-mail address: hensel{at}mikrobio.med.uni-erlangen.de
4 Abbreviations used in this paper: DC, dendritic cell; GLUT-1, glucose transporter-1; HIF, hypoxia inducible factor; LDH, lactate dehydrogenase; ns-siRNA, nonsilencing small interfering RNA; PFA, paraformaldehyde; PGK, phosphoglycerate kinase; PI, propidium iodide; siRNA, small interfering RNA.
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