Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis.
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.
Peyssonnaux
Carole
C
Division of Biological Sciences, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cejudo-Martin
Pilar
P
Doedens
Andrew
A
Zinkernagel
Annelies S
AS
Johnson
Randall S
RS
Nizet
Victor
V
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4