title: Moderate hypoxia potentiates interleukin-1β production in activated human macrophages.
abstract: BACKGROUND
  Inflammation drives atherogenesis. Animal and human studies have implicated interleukin-1β (IL-1β) in this disease. Moderate hypoxia, a condition that prevails in the atherosclerotic plaque, may conspire with inflammation and contribute to the evolution and complications of atherosclerosis through mechanisms that remain incompletely understood.
  
  
  OBJECTIVE
  This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1β production in activated human macrophages.
  
  
  RESULTS
  Our results demonstrated that hypoxia enhances pro-IL-1β protein, but not mRNA, expression in lipopolysaccharide-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1β to autophagic degradation, thus prolonging its half-life and promoting its intracellular accumulation. Furthermore, hypoxia increased the expression of NLRP3, a limiting factor in NLRP3 inflammasome function, and augmented caspase-1 activation in lipopolysaccharide-primed macrophages. Consequently, hypoxic human macrophages secreted higher amounts of mature IL-1β than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1β localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor 1α and hexokinase-2, as assessed by immunohistochemical staining of carotid endarterectomy specimens.
  
  
  CONCLUSIONS
  These results indicate that hypoxia potentiates IL-1β expression in cultured human macrophages and in the context of atheromata, therefore unveiling a novel proinflammatory mechanism that may participate in atherogenesis.
authors.affiliation: From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.affiliation: From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. plibby@partners.org.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta
keywords: autophagy; hypoxia; inflammasomes; inflammation; interleukins