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in Development of Lipopolysaccharide-Induced Sepsis1
,
* Division of Biological Sciences and
Department of Pediatrics, School of Medicine and
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093
Sepsis, the leading cause of death in intensive care units, reflects a detrimental host response to infection in which bacteria or LPS act as potent activators of immune cells, including monocytes and macrophages. In this report, we show that LPS raises the level of the transcriptional regulator hypoxia-inducible factor-1
(HIF-1) in macrophages, increasing HIF-1 and decreasing prolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting of HIF-1 in the myeloid lineage, we demonstrate that HIF-1 is a critical determinant of the sepsis phenotype. HIF-1 promotes the production of inflammatory cytokines, including TNF-, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1 deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1 activity may thus represent a novel therapeutic target for LPS-induced sepsis.
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 National Institutes of Health Grants CA82515 (to R.S.J.) and AI48694 (to V.N.) and an American Heart Association Established Investigator Award (to V.N.). A.Z. is supported by Swiss National Foundation Grant PPBZHB-108365 and P.C.-M. is supported by a fellowship from the Ministerio de Educacion y Ciencia (Spain).
2 Address correspondence and reprint requests to Dr. Randall S. Johnson, Molecular Biology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, MC 0377, La Jolla, CA 92093; E-mail address: rsjohnson{at}ucsd.edu or Dr. Victor Nizet, School of Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0687, La Jolla, CA 92093-0687; E-mail address: vnizet{at}ucsd.edu
3 Abbreviations used in this paper: HIF, hypoxia-inducible factor; PHD, prolyl hydroxylase; VEGF, vascular endothelial growth factor; WT, wild type.
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