Cutting Edge: Essential Role of Hypoxia Inducible Factor-1 in Development of Lipopolysaccharide-Induced Sepsis

Division of Biological Sciences, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2007; 178(12):7516-9. DOI: 10.4049/jimmunol.178.12.7516
Source: PubMed

ABSTRACT 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-1alpha (HIF-1alpha) in macrophages, increasing HIF-1alpha and decreasing prolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting of HIF-1alpha in the myeloid lineage, we demonstrate that HIF-1alpha is a critical determinant of the sepsis phenotype. HIF-1alpha promotes the production of inflammatory cytokines, including TNF-alpha, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1alpha deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1alpha activity may thus represent a novel therapeutic target for LPS-induced sepsis.

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Available from: Randall S Johnson, Mar 31, 2014
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    • "Murine myeloid specific knockouts of both HIF-1α and HIF-2α show distinct activities in regulating the immune response. Mice lacking myeloid HIF-1α show reduced migration and invasion of macrophages, limited acute inflammation, and inhibition of bactericidal activity (28–30). Mice lacking myeloid HIF-2α are resistant to endotoxemia and inflammatory lesions (31). "
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    • "Moreover, alteration in the gingival blood flow due to the reduced erythrocyte count might decrease the oxygen content in the gingival tissues [12]. Hypoxia produced as a result, induced the activation of the transcription factor hypoxia-inducible factor-1, triggering the expression of proinflammatory genes [37] and increased production of mitochondrial ROS, which activate the endothelial secretion of leukocyte adhesion receptors, thereby promoting the inflammatory response [38]. "
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    • "HIF-1␣ is a transcriptional factor that upregulates the expression of various genes in response to hypoxia, inflammation, and oxidative stress (Heyman et al. 2011). Lipopolysaccharides have been demonstrated to induce the expression of HIF-1␣ protein and HIF-1 dependent gene, even in the absence of hypoxia, in macrophages and the hepatic tissue of rats (Peyssonnaux et al. 2007; Kan et al. 2008). In animals subjected to LPS treatment, a significant increase in hepatic HIF-1␣ levels was probably due to LPS-induced tissue hypoxia and (or) the secretion of proinflammatory cytokines . "
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