Metabolic regulation of inflammatory processes: HIF-1? and IDO as anti-infectious effector molecules in professional phagocytes

The transcription factor Hypoxia-inducible factor (HIF)-1α mediates essential changes in gene expression to permit cellular adaptation to reduced oxygen supply. In addition, HIF-1α has direct anti-microbial functions, leading to the production of defensins, proteases and nitric oxide (NO). Hypoxia also enhances the enzymatic activity of the tryptophan-degrading heme enzyme indoleamine 2,3-dioxygenase-1 (IDO). It could be demonstrated that DC maturation is enhanced under hypoxic culture conditions, whereas IL-12p70 production is impaired in a HIF-1α-independent manner. In contrast, hypoxia-induced upregulation of CD73 and chemokine receptors CXCR4 and CCR7 were found to be HIF-1α-dependent in DC. Within the project two mutant mouse lines with efficient cell-type specific ablation of HIF-1α in DC, using either CD11cCre or CCL17Cre mice have been established and a mouse line overexpressing IDO is under construction. Within the new funding period the contribution of HIF-1α and IDO to antimicrobial defense and immune regulation will be determined.

Prof. Dr. Irmgard Förster
Institute of Environmental Health Research (IUF) Düsseldorf

TP5 in period 2007-2009

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