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Hypoxia and hypoxia-Inducible Factor-1\alpha Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function

Janstch, Jonathan and Charkavortty, Dipshikha and Turza, Nadine and Prechtel, Alexander T and Buchholz, Björn and Gerlach, Roman G and Volke, Melanie and Gläsner, Joachim and Warnecke, Christina and Wiesener, Michael S and Eckardt, Kai-Uwe and Steinkasserer, Alexander and Hensel, Michael and Willam, Carsten (2008) Hypoxia and hypoxia-Inducible Factor-1\alpha Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function. In: Journal of Immunology, 180 (7). pp. 4697-4705.

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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\alpha (HIF-1\alpha), are largely unknown. Thus, we investigated the effects of hypoxia and HIF-1alpha 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\alpha protein levels, induction of glycolytic HIF target genes, and enhanced glycolytic activity. Using RNA interference techniques, knockdown of HIF-1alpha 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\alpha and hypoxia play a crucial role for DC activation in inflammatory states, which is highly dependent on glycolysis even in the presence of oxygen.

Item Type: Journal Article
Publication: Journal of Immunology
Publisher: American Association of Immunologiests
Additional Information: Copyright of this article belongs to American Association of Immunologiests.
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 16 Jul 2008
Last Modified: 03 Nov 2008 09:50
URI: http://eprints.iisc.ac.in/id/eprint/14994

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