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Hypoxia-Inducible Factor (HIF) 1 Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance¹

Institut für Physiologie, Universität Duisburg-Essen, Essen, Germany

The oxygen-sensitive transcription factor hypoxia-inducible factor 1 (HIF-1) is known as the key regulator of hypoxia-induced gene expression. In addition to hypoxia, endotoxins such as bacterial LPS as well as proinflammatory cytokines have been shown to induce HIF-1, suggesting an integrative role for HIF-1 in conditions of hypoxia and inflammation. Cells can become tolerant to endotoxins by repetitive exposure to LPS. Herein, we studied the effect of endotoxin tolerance on HIF-1 accumulation and expression of HIF target genes in human monocytic cells and primary mouse peritoneal macrophages. Tolerant cells had reduced levels of HIF-1 under hypoxia, which was due to lowered levels of HIF-1 mRNA. HIF-1 expression is under control of NF-B and increased DNA binding of the p52 subunit of NF-B was found in tolerant cells. Knock down of p52 abolished the effects of endotoxin tolerance on HIF-1 expression, which suggest a negative regulatory role of p52 on HIF-1 transcription during endotoxin tolerance. Endotoxin tolerant cells showed diminished expression of the HIF target genes phosphoglycerate kinase 1 and adrenomedullin and reduced viability under hypoxic conditions, as well as a significantly reduced invasion. Peritoneal macrophages from endotoxin-tolerant mice made showed significantly reduced HIF-1 protein accumulation and subsequent HIF target gene expression. We conclude that endotoxin tolerance impairs HIF-1 induction which reduces the ability of monocytic cells to survive and function under hypoxic conditions.

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 work was supported by the Deutsche Forschungsgemeinschaft (FA 225/21).

² Address correspondence and reprint requests to Dr. Joachim Fandrey, Institut für Physiologie, Universität Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany. E-mail address: joachim.fandrey{at}uni-due.de

³ Abbreviations used in this paper: HIF-1, hypoxia-inducible factor 1; siRNA, small interfering RNA; PGK1, phosphoglycerate kinase 1; ADM, adrenomedullin.