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 Blood, 3 September 2009, Vol. 114, No. 10, pp. 2140-2148.
Prepublished online as a Blood First Edition Paper on June 23, 2009; DOI 10.1182/blood-2009-01-201889.

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IMMUNOBIOLOGY

The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor–1{alpha} in macrophages via sphingosine-1-phosphate and transforming growth factor-β

Barbara Herr1, Jie Zhou1, Christian Werno1, Heidi Menrad1, Dmitry Namgaladze1, Andreas Weigert1, Nathalie Dehne1, and Bernhard Brüne1

1 Institute of Biochemistry I, Faculty of Medicine, Goethe-University, Frankfurt, Germany

Macrophages infiltrating solid tumors exhibit a tumor-supporting phenotype and are critical for tumor development. Little is known which tumor-derived signal provokes this phenotype shift and how these signals are interpreted in macrophages to support tumor growth. We used the supernatant of apoptotic cells and noticed transcriptional, nuclear factor of activated T cells-dependent up-regulation of hypoxia-inducible factor (HIF)–1{alpha} mRNA, subsequent protein expression, and HIF-1 activity. Blocking calcineurin with cyclosporine A attenuated nuclear factor of activated T cells binding during electrophoretic mobility shift assay analysis and circumvented the HIF-1{alpha} mRNA increase. Knockdown experiments, receptor analysis, and antibody neutralization pointed to sphingosine-1-phosphate and transforming growth factor-β as the initiators of the HIF-1 response. The use of macrophages from conditional HIF-1{alpha} knockout mice revealed that macrophages, under the impact of apoptotic cell supernatants, use HIF-1 to produce factors that induce CD31 expression in murine embryonic stem cells. Our study supports the notion that soluble factors produced from apoptotic tumor cells activate the HIF-1 system under normoxia in macrophages to enhance their tumor-promoting capacity by, for example, releasing vascular endothelial growth factor. This shows the importance of HIF-1–elicited responses in regulatory macrophages under normoxia.


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