Toll-like receptor activation and hypoxia use distinct signaling pathways to stabilize hypoxia-inducible factor 1α (HIF1A) and result in differential HIF1A-dependent gene expression

Journal of Leukocyte Biology

Roland Lang³  Kai-Uwe Eckardt¹  Markus Schnare–, and⁶  Joachim Gläsner³  Sophie Kolbe³  Michael Hensel⁴  Jonathan Jantsch³  David Mole⁵  Carsten Willam ¹  Johannes Schödel²  Kirstin Castiglione³  Christian Bogdan³  Ulrike Schleicher³  Melanie Wiese³ 

[1]  Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;; Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany; Henry Wellcome Building of Molecular Physiology, University of Oxford, United KingdomMikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, and  Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;Abteilung für Mikrobiologie, Universität Osnabrück, Germany;Henry Wellcome Building of Molecular Physiology, University of Oxford, United Kingdom  Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;–Institut für Immunologie, Philipps-Universität Marburg, Germany;

关键词: dendritic cells;    poly I:C;    CpG;    LPS;    MYD88;    TRIF;    NOS2;    PTGS2;    HIF;   

DOI  :  10.1189/jlb.1210683

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

HIF1A is a transcription factor that plays a central role for the adaptation to tissue hypoxia and for the inflammatory response of myeloid cells, including DCs. HIF1A is stabilized by hypoxia but also by TLR ligands under normoxic conditions. The underlying signaling events leading to the accumulation of HIF1A in the presence of oxygen are still poorly understood. Here, we show that in contrast to hypoxic stabilization of HIF1A, normoxic, TLR-mediated HIF1A accumulation in DCs follows a different pathway that predominantly requires MYD88-dependent NF-κB activity. The TLR-induced HIF1A controls a subset of proinflammatory genes that are insufficiently induced following hypoxia-mediated HIF1A induction. Thus, TLR activation and hypoxia stabilize HIF1A via distinct signaling pathways, resulting in differential HIF1A-dependent gene expression.

【 授权许可】

Unknown